|Ahead of print publication
B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer
Qipeng Liu1,2, Qiaqia Li1,2, Sen Zhu1, Yang Yi1,3,4, Qi Cao1,5,6
1 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA
2 Xiangya School of Medicine, Central South University, Changsha 410008, China
3 Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China
4 Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
5 Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA
6 Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
|Date of Submission||18-Dec-2017|
|Date of Acceptance||17-Apr-2018|
|Date of Web Publication||01-Jun-2018|
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA
Source of Support: None, Conflict of Interest: None
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
Keywords: B lymphoma Moloney murine leukemia virus insertion region 1; oncogene; polycomb repressive complex 1; prostate cancer
Article in PDF
|How to cite this URL:|
Liu Q, Li Q, Zhu S, Yi Y, Cao Q. B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer. Asian J Androl [Epub ahead of print] [cited 2019 Jan 23]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=233684
| Introduction|| |
Prostate cancer (PCa) is the second most commonly diagnosed cancer affecting men worldwide. The incidence of PCa in the developed world is strikingly higher than that in developing countries. In the United States, PCa is the most prevalent malignancy and the third fatal carcinoma to cause cancerous mortality among males. Despite the conspicuous medical advances including surgery and radiotherapy amongst the current treatment options, PCa still poses a great medical challenge to clinicians and researchers. Patients diagnosed with early-stage PCa are treated with radical or partial prostatectomy and combined local radiation therapy. Whereas androgen deprivation therapy (ADT) remains the mainstream treatment for advanced and metastatic PCa and demonstrates benefits and better survival for patients, a considerable portion of tumors will inevitably evolve into castration-resistant prostate cancer (CRPC). Androgen and androgen receptor (AR)-directed therapies such as abiraterone acetate and enzalutamide (MDV3100) are initially effective in treating CRPC. Typical chemotherapy drug docetaxel, combined with prednisone, also demonstrated positive therapeutic effects on clinical treatments on CRPC and advanced refractory PCa. However, PCa tumors will eventually develop drug resistance in which AR signaling plays a critical role. The possible mechanisms include AR amplification, mutations, and activation.,, Prostate cancer stem cells, which are resistant to most standard therapies, are also considered to be a major mechanism of cancer progression and recurrence. Other mechanisms such as epithelial–mesenchymal transition (EMT) and alteration of glucocorticoid receptor (GR) are also reported to be key players of the advanced PCa., Metastasis and relapse will cause high mortality among those patients.
PCa is defined as a multifactorial disease since the comprehensive understanding of its etiology remains elusive. Age and genetic predisposition rank as the top risk factors. Latest studies have discovered that epigenetic aberrations also play an indispensable role in the tumorigenesis of PCa. The epigenetic changes are the result of postreplication modification in DNA and/or posttranslational modification of DNA-associated proteins. B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a widely known epigenetic regulator in a series of physiological stemness-associated functions, is also found to exert its oncogenic effects during the onset of malignant changes. BMI1 was isolated as an oncogene that cooperates with c-MYC, a proto-oncogene, in the oncogenesis of murine lymphomas. Furthermore, BMI1 transcriptionally represses p16Ink4A and p19/p14Arf, two tumor suppressors coded by Ink4a/Arf (CDKN2A) with regard to their effects to curb cell proliferation in response to aberrant mitogenic signaling.,,
BMI1 plays a critical role in the regulation of gene expression and cellular processes, including cell cycle progression, DNA damage repair, EMT, as well as self-renewal, differentiation, and malignant transformation of stem cells. Following the intimate correlation between BMI1 overexpression and malignancy, the fact that BMI1 serves as an oncogenic regulator inspires researchers to develop new promising therapeutic approaches. In the context of PCa, tumors with high malignant grades are highly correlated with corresponding upregulation of BMI1 detected in tumor specimens. As an indicator of poor clinical outcome, BMI1 is more of a multifaceted regulator in the network of genetic and epigenetic modifications. This review accordingly aims to provide a comprehensive overview of the relevance and involvement of BMI1 in PCa initiation, progression, recurrence, and potential therapeutic approaches.
| BMI1 as a Core Component of Polycomb Repressive Complex 1 (PRC1)|| |
Two common assets of epigenetic modifiers known as trithorax group (TrxG) and polycomb group (PcG) are respectively responsible for transcriptional activation and repression., PcG proteins form mainly two large multimeric polycomb repressive complexes which are, namely, PRC1 and PRC2. In the company of other epigenetic regulators, these two complexes silence downstream genes through histone tail posttranslational modifications., BMI1 is one of the core components of PRC1 together with RING1A (RNF1 or RING1), RING1B (RNF2 or RING2), chromobox proteins (CBXs), and other variable subunits. RNF2 functions as an E3 ubiquitin ligase and monoubiquitylates histone 2A at lysine 119 residue (H2AK119ub) and thus subsequently represses the expression of downstream targets. BMI1 was a cofactor to stimulate the ubiquitylating activities of RNF2. Collaborating with other polycomb group allies, BMI1 functions as an epigenetic repressor which remodels chromatin by the monoubiquitination of histone 2A at lysine 119 and subsequent methylations at histone.BMI1 was first identified in 1991 as a frequent target of Moloney virus insertion in virally accelerated B-lymphoid tumors of E mu-myc transgenic mice. BMI1 represses the INK4a/ARF tumor suppressor which encodes the p16Ink4a and p19/p14Arf.,
Gene and protein structure of BMI1
BMI1 was initially isolated as an oncogene which collaborates with c-Myc in the tumorigenesis of murine retrovirus-induced leukemia.,BMI1, which is composed of 9 introns and 10 exons, is localized on the short arm of chromosome 10 (10p11.23) and extends over 10 kb [Figure 1]a. Human BMI1 protein is highly conserved and composed of 326 amino acids. BMI1 has a species-conserved N-terminal RING finger, a central helix-turn-helix (HTH) domain, a C-terminal proline-glutamic acid-serine-threonine (PEST) domain, and two nuclear localization signal (NLS) motifs KRRR and KRMK [Figure 1]b. The N-terminal RING motif of BMI1 does not endow BMI1 with E3 ligase abilities, but its association with RING1B is required for enhancing the E3 ligase activities of RING1B., The HTH domain is significant for BMI1 localization at DNA strand break and crucial for the recruitment of DNA damage repair and inhibition of cellular senescence.,,, The PEST domain, which is namely rich in proline (P), glutamic acid (E), serine (S), and threonine (T), is necessary for BMI1 protein turnover. PEST domain also inhibits BMI1 degradation and thus promotes its oncogenic capacities including EMT.
|Figure 1: Gene and protein structure of human BMI1. (a) BMI1 gene consists of 10 exons and 9 introns. (b) BMI1 protein starts from N-terminal RING domain required for interaction with RING1A/B, two NLS domains, HTH domain required for BMI1 localization at DNA damage site, to C-terminal PEST which is critical for BMI1 turnover. BMI1: B lymphoma Moloney murine leukemia virus insertion region 1; NLS: nuclear localization signal; HTH: helix-turn-helix; PEST: proline-glutamic acid-serine-threonine.|
Click here to view
| BMI1 Expression and Regulation|| |
BMI1 is ubiquitously expressed in nearly all organs and tissues and highly expressed in the brain, spinal cord, thymus, lungs, kidneys, blood, bone marrow, gonads, placenta, and stem cells of diverse lineages. Its expression is observed to be elevated in many cancer subtypes. BMI1 is involved in many physiological and pathological processes, and thus its transcription and expression levels are tightly regulated by diverse factors [Table 1].
|Table 1: Regulators of B lymphoma Moloney murine leukemia virus insertion region 1 and their functions|
Click here to view
BMI1 is regulated by many transcription factors and epigenetic regulators. Transcription factor twist family bHLH transcription factor 1 (TWIST1), zinc finger E-box binding homeobox 1 (ZEB1), E2F transcription factor 1 (E2F1), c-Myc, N-Myc, Sp1 transcription factor (Sp1), spalt-like transcription factor 4 (SALL4), and NANOG positively regulate BMI1 expression. TWIST1 directly regulates BMI1 transcription, whereas ZEB1 indirectly upregulates BMI1 by repressing miR-200. TWIST1 and ZEB1 also are EMT promoting transcription factors. C-Myc and N-Myc were shown to upregulate BMI-1 mRNA by binding to the E-box within the BMI1 promoter in a dose-dependent manner. E2F1 was reported to regulate BMI1 and PRC2 components, but not other PRC1 subunits. Sp1 and SALL4 bind to the BMI1 promoter and thus upregulate its expression., NANOG, a transcription factor critically involved with self-renewal of embryonic stem cells, was reported to positively regulate BMI1 by binding to its promoter. BMI1 expression was shown to be suppressed by Kruppel-like factor 4 (KLF4), Mel-18 (polycomb group ring finger 2 [PCGF2]), and histone deacetylase inhibitors (HDACi).,,
More importantly, posttranscriptional regulations of BMI1 mRNA enable its maturation, transport to the correct loci, and final translation of its encrypted information to protein. Such regulations require the interaction of RNA binding protein with mRNA elements localized within 5'- and 3'- untranslated regions (UTRs) of precursor mRNA (pre-mRNA). The 5'- and 3'-UTRs are also subject to pharmacological inhibition. Moreover, microRNAs (miRNAs) also participate in the repression of mRNA translation by either silencing or directly degrading the target mRNA. Dysregulation of BMI1 associated miRNAs is often related to disordered cancer cell proliferation. During prostate carcinoma progression, miR-128, -200b, -200c, -221, -30d, -15a, and -16 have been reported to suppress the overall pathogenesis of PCa through targeting BMI1.,,,, These miRNAs are tumor suppressors which may be potential clinical classification biomarkers and therapeutic targets in PCa. BMI1 plays a critical role in epigenetic modification by posttranscriptional regulation of miRNAs.
Posttranslational regulation is also crucial for the physiologic functions of BMI1. AKT kinase phosphorylates BMI1 and enhances its oncogenic potential in an Ink4a/Arf-independent manner in PCa. CBX4 mediates BMI1 sumoylation at lysine 88 to enhance its recruitment at damaged DNA sites. Furthermore, BMI1 directly interacted with O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), an enzyme which catalyzes the O-linked beta-N-acetylglucosamine (O-GlcNAcylation), an uncommon type of posttranslational modification. O-GlcNAcylation inhibits BMI1 from degrading via ubiquitin proteasomal degradation pathway and therefore stabilizes BMI1 protein and enhances its oncogenic potential.
| The Clinical Features of BMI1 in Prostate Cancer|| |
Increasing evidence suggests that BMI1 is highly correlated with unfavorable prognosis, low survival, and poor outcome of cancer. BMI1 overexpression was first discovered to be associated with poor prognosis in hematopoietic malignancies,, since then its elevation has been reported in a plethora of cancer types including nonsmall cell lung cancer, gastric cancer, nasopharyngeal carcinoma, breast cancer, as well as PCa., According to the broad microarray analyses, BMI1 serves as a diagnostic and prognostic biomarker predicting metastasis, chemotherapy resistance, and tumor recurrence in a plethora of cancer types.,
The oncogenic capacities of BMI1 have been unveiled in PCa. Elevation of BMI1 mRNA was detected in human PCa cell lines, xenografts derived from PCa cells and human PCa specimens. PCa with adverse pathologic and clinical features is highly correlated with BMI1 overexpression. Tumors graded with Gleason scores of 8 or higher are associated with significant upregulation of BMI1, and the presence of BMI1 in lower grade PCa specimen is highly predictive for prostate-specific antigen (PSA) recurrence. Microarray meta-analyses have discovered that the presence of BMI1 in PCa specimens often indicates tumor metastasis and poor prognosis. The study also identified a BMI1 pathway with concordant profiles in PCa metastasis. BMI1 was observed to be enriched in a population of PCa cells with higher tumor initiating capacities. Also, BMI1 expression was highly correlated with the therapy failure and poor survival in five types of epithelial tumors including PCa.
Lack of predictive biomarkers for diagnosing and monitoring PCa has been a medical challenge. Although PSA has been widely recognized as the biomarker for the diagnosis, surveillance, and prognosis of PCa, it has several disadvantages such as inadequate sensitivity and bias of racial and ethnic differences. Secretory BMI1 protein has been discovered to be a conceivably reliable serum biomarker for the diagnosis, progression monitoring, and prognosis of human PCa.
| BMI1 in Tumor Initiation with Regard to Normal Stem Cells|| |
Stem cells are generally divided into two types: embryonic stem cells (ESCs) and adult stem cells (ASCs). ESCs, derived from the blastocyst in early mammalian embryos, are pluripotent stem cells that can differentiate into any cell types. BMI1 is highly expressed in ESCs and associated with morphogenesis during embryonic development. Bmi1-null mutant mice exhibited neurological abnormalities, hematopoietic defects, and lymphatic dysplasia.
Most adult tissues harbor stem cells responsible for the self-regeneration and differentiation to maintain homeostasis and repair after tissue injury. BMI1 has been implicated in the modulation of self-renewal in ASCs of several lineages. A potential association between BMI1 and stem cell properties was suggested after increased BMI1 mRNA levels were observed in adult human hematopoietic stem cells (HSCs). Besides, defective self-renewal capability of HSCs was detected in Bmi1-/- mice. BMI1 was found highly expressed in human HSCs and then decreased when HSCs differentiate into certain lineages. Similarly, it has been reported that BMI1 plays an essential role in the self-renewal and pluripotency of neural stem cells (NSCs). Downregulation of BMI1 could cause compromised self-renewal and propagating capacities in NSCs both in vivo and in vitro.
The prostate is a glandular and solid organ whose development highly relies on the serum androgen level. Normally, mature prostatic epithelium consists of three basic cell types: basal, luminal (secretory), and neuroendocrine which are distinguished from their specific marker expression and corresponding features. Basal cells, which are located on the basement membrane in prostatic epithelium, are characterized by the expression of cytokeratin 5 and 14 (CK5 and CK14), CD44, and p63.,,,, A small-scale population of basal cells has been recognized as the prostate stem cells (PrSCs). PrSCs have the self-renewal abilities, and they can differentiate into luminal cells, induce tissue regeneration, and also play an important role in tumor initiation. PrSCs are more likely to survive ADT and propagate in castrated mice. BMI1 mRNA levels were observed to be 7-fold higher in the basal/stem cell population than in the luminal cells. Immunohistochemical analyses of adult prostate sections showed that BMI1 overexpression was in line with the coexpression of the basal marker CK5, which demonstrates that BMI1 enriches in the PrSCs and executes their maintenance. It has been reported that BMI1 marked a population of luminal epithelial cells that exhibited prostate regenerative and cancer initiating potential as well as the castration-resistance.
| BMI1 in Prostate Cancer Progression and Recurrence|| |
The mechanism of progression and recurrence of PCa are complicated. Cancer stem cells (CSCs) transformation and EMT, in which BMI1 plays a pivotal role, facilitate diverse phenotypes of tumor cells and enhance the capacities of metastasis and drug resistance. Besides, BMI1 is also involved in cellular processes such as cell cycle progression and DNA damage repair., Whereas numerous current chemotherapy drugs are targeting cell cycle and DNA repair, BMI1 overexpression has been proven to be involved in corresponding chemoresistance., Overall, BMI1 is an oncogenic regulator in the complicated mechanism network of PCa progression and recurrence [Figure 2].
|Figure 2: Schematic representation of BMI1 participation in the initiation, progression, and relapse of prostate cancer. ADT: androgen deprivation therapy; AR: androgen receptor; BMI1: B-cell-specific MMLV insertion region 1; CRPC: castration-resistant prostate cancer; PRC1: polycomb repression complex 1; PTEN: phosphatase and tensin homolog; hTERT: human telomerase reverse transcriptase; TOP2A: topoisomerase 2-alpha.|
Click here to view
Cancer stem cells
Tumor tissues are composed of heterogeneous groups of cells. CSCs are cancer cells that possess characteristics as normal stem cells, specifically the abilities to differentiate into all cell types in a particular tumor sample. The pluripotency of CSCs remarkably enhances the capacities to give rise to heterogeneous phenotypes; therefore, the tumor recurrence subsequent to tumor shrinkage is inevitable in the conventional treatments as chemotherapies and radiotherapies. Metastasis and tumor relapse are highly unmanageable due to the substantial resilience of CSCs. Evidences have indicated that BMI1 is crucial for the self-renewal and differentiation of CSCs. BMI1 is also reported to be crucial for the self-renewal, proliferation, and differentiation of leukemia stem cells (LSCs). Intriguingly, BMI1-expressing LSCs were prone to inducing leukemia when transplanted into irradiated mice. On the contrary, BMI1-null LSCs presented limited proliferative and tumorigenic potential. Similarly, BMI1 has been proposed to maintain the self-renewal and pluripotency of bronchioalveolar CSCs  and breast cancer stem cells. Besides, BMI1 has been demonstrated as a downstream gene in the Hedgehog signaling pathway, which is known to be associated with the self-renewal, differentiation, and canceration of breast and prostate stem cells.,, Patients diagnosed with PCa are often treated with ADT. Although this treatment is mostly followed by the androgen independence and recurrence of PCa, the resolution to CRPC may lie in the PCa stem cells, which have the ability to survive ADT and replenish the tumor with cells which have more aggressive phenotypes.
The EMT is the primary mechanism in which cancer cells acquire malignant phenotypes that induce metastasis and recurrence. EMT in cancer cells causes many adverse alterations including loss of epithelial cell marker, activation of specific growth factors, and gain of mesenchymal phenotypes. Cancer cells which have experienced EMT exhibit similar characteristics as CSCs., BMI1 plays a crucial part in the process of EMT. Upregulation of BMI1 represses the tumor suppressor phosphatase and tensin homolog (PTEN) by which BMI1 induced EMT and enhanced the invasiveness and metastasis of human nasopharyngeal epithelial cells, whereas silencing BMI1 expression reversed EMT. TWIST1 is a significant EMT marker which positively regulates BMI1 expression. The knockdown of either TWIST1 or BMI1 blocked both EMT and stem-like properties, indicating that BMI1 is essential as a downstream target of TWIST1 during EMT.
The normal cell cycle progression consists of four phases and its regulation demands cell cycle checkpoints to ensure the accurate division. BMI1, being a PcG protein and transcriptional repressor, also plays an important role in cell cycle regulation. BMI1 promotes cell proliferation through the critical cell-cycle control locus Ink4a/Arf. It negatively regulates tumor suppressors p16 and p19Arf which induce G1 and G2 phase arrest., CDK4/6 activity and pRb-p53 pathway are promoted by BMI1 repressing p16 and p19Arf. Primary embryonic fibroblasts deficient of Bmi1 were impaired in cell cycle progression and underwent premature senescence. BMI1 also directly regulates p53 stability, which is independent of Ink4a/Arf locus, further enhancing its duties in cell cycle progression and cellular proliferation., Docetaxel causes cell cycle arrest and blocks mitosis by inhibiting mitotic spindle assembly. BMI1 was reported to mediate docetaxel chemoresistance in PCa, and silencing BMI1 enhances the sensitivity of PCa cells to docetaxel.
DNA damage repair
Genome integrity is vulnerable to intra- and extracellular sources such as oxidative particles generated by metabolic activities and environmental radiation. DNA damage repair is a series of processes by which cells identify and rectify the damage to the genome structure. The crucial role of BMI1 has been demonstrated in the cellular response to DNA damage. BMI1 is recruited to DNA breaks and enriched at the chromatin after irradiation. BMI1 tethers RING1B to DNA lesions and further stimulates H2A ubiquitination and subsequent DNA repair. While some polycomb proteins, including MEL18, CBX6, CBX7, and CBX8, have been reported to be recruited to the DNA damage sites in a poly(ADP ribose) polymerase (PARP)-dependent manner, the localization of BMI1 has been proven to be independent upon PARP1. DNA topoisomerase 2-alpha (TOP2A) covalently binds to double strand DNA breaks, and then TOP2A-DNA cleavage complex forms DNA lesions to trigger cell cycle arrest and cell death. BMI1/RING1A complex degraded TOP2A cleavage complex; therefore, inhibiting the E3 ligase activities of BMI1/RING1A significantly increased antitumor potency of TOP2 drugs. BMI1 enhanced telomerase activity by upregulating human telomerase reverse transcriptase (hTERT) to induce PCa immortalization, which is another mechanism to exhibit BMI1's oncogenic capacities.
These observations collectively suggest that BMI1 emerges as an inherent regulator for the maintenance of both normal stem cells and cancer stem cells. BMI1 is at the crossroads of physiological processes and malignant alterations. This suggests that BMI1 may play a pivotal role in the progression of PCa.
| BMI1 and AR Signaling Pathway in Prostate Cancer|| |
PCa therapy highly depends on androgen signaling pathway blockage considering that AR signaling pathway is profoundly involved in initiation, progression, and relapse of PCa. AR, also known as nuclear receptor subfamily 3, group C, member 4 (NR3C4), belongs to nuclear receptors that are activated by steroid hormones as testosterone and 5α-dihydrotestosterone (DHT). AR consists of three major functional domains: the N-terminal domain (NTD), the DNA binding domain (DBD), and the C-terminal ligand binding domain (LBD). Intracellularly, testosterone and DHT exert their biological effects through binding to AR, which results in translocation of AR into the nucleus. In the nucleus, receptor dimers bind to androgen response elements (AREs) in the promoter of target genes (e.g., PSA and transmembrane serine protease 2 [TMPRSS2]) and modulate their expression, leading to responses such as PCa maintenance and differentiation.
The AR signaling pathway is intimately linked to normal development and functioning of the prostate, moreover, cancerous progression. Recent evidence suggests that 159 mutations found in AR gene are correlated with PCa. Research also indicates that shorter AR CAG repeats in NTD may lead to greater risk of PCa in males. Most prostate tumors are dependent on androgen at initial diagnosis, making ADT the favored treatment to block the AR signaling and cause cancer cell death. However, patients may gradually develop hormone-refractory disease (CRPC). Four possible mechanisms of CRPC development are proposed as increased sensitivity of the AR to its agonists, AR mutations that render the receptor responsive to alternate nonandrogen ligands, ligand-independent AR activation, and other AR-independent mechanisms. AR splice variants (AR-Vs) are identified in cell lines and tumor tissues derived from patients with CRPC. The presence of AR-V7 is strongly associated with drug resistance in a cohort study. By detecting AR-V7 in circulating tumor cells with reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) assay and examining PSA level in patients, AR-V7-positive patients were found to express higher AR mRNA and PSA and were more likely to have lower Easten Cooperative Oncology Group (ECOG) performance score and unfavorable clinical outcome from enzalutamide and abiraterone therapy. While AR variants, including but not limited to AR-V7 and AR-Ve567s, play a crucial role in CRPC indisputably, the molecular mechanisms downstream of AR that mediate CRPC have not been comprehensively revealed.
A few studies have focused on the relation between PcG proteins and AR signaling pathway. EZH2 expression was proven to be repressed by androgens through retinoblastoma (RB) and p130-dependent pathways. Higher protein levels of BMI1 were detected in androgen-independent PC3 and DU145 cells compared to androgen-dependent LNCaP cells, which implies that BMI1 might exert its oncogenic effects by participating in AR signaling pathway. Despite the fact that BMI1 and AR are both abundantly expressed in PCa cells, the association between BMI1 and AR has remained unclear until very recently a study reported that BMI1, independently of the PRC1 complex, binds and stabilizes AR proteins to regulate the AR pathway in PCa. According to this study, AR protein levels together with the protein and transcript levels of AR-activated targets, such as PSA and TMPRSS2, were downregulated after depletion of BMI1 in AR-positive PCa cells; meanwhile, AR-repressed targets were increased, suggesting that BMI1 acts as a transcriptional activator through its binding with AR. IP-IB analysis revealed that AR-NTD, but not other two domains, is essential for AR-BMI1 interaction. Besides, BMI1 compromised the interaction between AR-NTD and MDM2 dose dependently, confirming that BMI1 competitively inhibits the interaction between MDM2 and the AR-NTD. In addition, BMI1 interacts with AR-V7, AR-Ve567s, and other AR variants since all AR variants contain the AR-NTD domain. Moreover, targeting BMI1 could significantly inhibit tumor growth of xenografts which were resistant to castration and enzalutamide treatment. In conclusion, BMI1 is a potential and novel therapeutic target for CRPC.
| Pharmacological Targeting of BMI1|| |
As discussed above, BMI1 exerts oncogenic functions during cancer progression, and it is presumably concluded that BMI1 targeting should have quintessential antitumor effects. 2-pyridine-3-yl-methylene-indan-1,3-dione (PRT4165), a PRC1 inhibitor, was discovered as a molecule inhibitor of BMI1/RING1B-mediated polyubiquitylation as it inhibited E3 ligase activities of PRC1. PRT4165 has synergistic effects with anthracyclines to increase the persistence of TOP2A-DNA cleavage complex. However, PRT4165 only targets the PRC1-dependent enzymatic activities of BMI1 and does not affect the expression levels of BMI1.
Knocking down BMI1 on tumor cells with small hairpin RNA (shRNA) inhibited cell growth and efficiently reversed the status of chemoresistance. PTC-209, a novel small molecule inhibitor of BMI1, has been reported to reduce BMI1 expression through selectively targeting the BMI1 transcript via its 3'-UTR. The anticancer effects of PTC-209 were mediated by cell cycle exit and subsequent apoptosis in colorectal cancer stem cells. Most cancer chemotherapies are aimed at the cell cycle. The cell cycle arrest has further been investigated in biliary tract cancer cells. Under PTC-209 treatment, most cells were arrested in the G0/G1 phase of the cell cycle and cells in the S-phase were significantly reduced. Breast cancer 1, early onset (BRCA1), meiotic recombination 11 homolog A (MRE11A), and RAD51 recombinase (RAD51), which are responsible for the DNA repair machinery, were observed to be inhibited by PTC-209 treatment., Both the transcript levels and protein levels of BMI1 in lung cancer cell lines were downregulated upon PTC-209 treatment. Targeting of BMI1 with PTC-209 also showed potent therapeutic effects in multiple myeloma.
Treatment of human PCa cells, stem cells, and patient-derived stem cells with PTC-209 induced BMI1 downregulation and subsequent inhibitory effects on cell proliferative abilities. BMI1 expression is tightly controlled by posttranscriptional processes mapping to the 5'- and 3'-UTRs. PTC-209 exerts its antiproliferative effects by directly modulating BMI1's posttranscriptional mechanisms. PTC-209 could directly bind to the pockets formed in the BMI1 RNA fold structure, and BMI1 UTR luciferase reporter assay was utilized to indicate that PTC-209 selectively inhibits the BMI1 UTR-regulatory reporters. PTC-209 treatment critically reduces BMI1 protein levels, but not a panel of 245 kinases and 21 phosphatases that may exhibit epigenetic capacities. PTC-209 impaired both the cell survival and clonogenic capacities in therapy-resistant PCa and pharmacologically inhibited the tumor growth in mouse xenografts of PCa tumor cells.
PTC596, a well-tolerated drug currently in phase I clinical trial, has shown higher specificity of BMI1 inhibition and less side effects in animal cancer models. PTC596 induced degradation of BMI1 and eventually caused CSC depletion. PTC596 has been proven to downregulate MCL-1 and induces p53-independent apoptosis in acute myeloid leukemia progenitor cells.
We have implied that BMI1 level is predictive for the malignancy and poor prognosis of PCa.,, Thus, pharmacological inhibition of BMI1 impedes cancer progression and therefore is a promising strategy for targeting PCa, especially after hormone therapy resistance.
| Conclusions|| |
Mounting evidence has indicated that BMI1, the key component of PRC1, plays a pivotal oncogenic role in the tumor initiation, progression, and relapse of prostate cancer, as well as many other cancer categories. BMI1 dysregulation has been associated with evolution and progression of a cohort of carcinoma subtypes mostly by endowing tumor cells with proliferative capacities. This review elucidates the oncogenic functions of BMI1 identified in prostate cancer. BMI1 is a critical oncogenic modulator involved in the initiation, progression, and relapse of prostate cancer. BMI1 is also a biomarker for the clinical diagnosis, management, and prognosis as well as a therapeutic target in therapy-resistant prostate cancer. BMI1 inhibitors such as PTC209 and PTC596 have demonstrated potent therapeutic effects on several types of solid tumors including prostate cancer. In spite of noteworthy progress made on pharmacological targeting of BMI1, the treatment of advanced-stage prostate cancer necessitates further development on drugs with higher specificity and less adverse effects.
BMI1 is a transcriptional silencer as a collaborator of RING1B to enhance its E3 ligase activities. The interaction between BMI1 and AR signaling pathway has been demonstrated to occur in absence of other PRC1 members, implying that BMI1 may have multiple functions in PRC1-independent manner. The capacities of BMI1 which are independent of PRC1 have yet to be revealed.,,,,,,,,,,,,,,,,,,,
| Author Contributions|| |
Qipeng Liu reviewed literature and drafted the manuscript. Qiaqia Li created the figures. SZ, YY, and QC edited the manuscript. QC supervised the whole work. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declared no competing interest.
| Acknowledgments|| |
This work is supported in part by grants from Houston Methodist Research Institute, Prostate Cancer Foundation (13YOUN007 to QC), U.S. Department of Defense (W81XWH-15-1-0639 and W81XWH-17-1-0357 to QC), American Cancer Society (TBE-128382 to QC), and NIH/NCI (1R01CA208257 to QC).
| References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin
2017; 67: 7–30.
Carson CC 3rd
. Carcinoma of the prostate: overview of the most common malignancy in men. N C Med J
2006; 67: 122–7.
PDQ Adult Treatment Editorial Board. Prostate Cancer Treatment (PDQ ®
): Health Professional Version. In: PDQ Cancer Information Summaries. Bethesda: National Cancer Institute (US); 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK66036/
. [Last accessed on 18 May 2018].
Shaw GL, Wilson P, Cuzick J, Prowse DM, Goldenberg SL, et al.
International study into the use of intermittent hormone therapy in the treatment of carcinoma of the prostate: a meta-analysis of 1446 patients. BJU Int
2007; 99: 1056–65.
Shapiro D, Tareen B. Current and emerging treatments in the management of castration-resistant prostate cancer. Expert Rev Anticancer Ther
2012; 12: 951–64.
Nagao K, Matsuyama H. [Docetaxel chemotherapy against CRPC]. Nihon Rinsho
2016; 74 Suppl 3: 619–23. [Article in Japanese].
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, et al. In vivo
amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet
1995; 9: 401–6.
Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res
2001; 61: 2892–8.
Wang Q, Li W, Zhang Y, Yuan X, Xu K, et al.
Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell
2009; 138: 245–56.
Lawson DA, Xin L, Lukacs R, Xu Q, Cheng D, et al.
Prostate stem cells and prostate cancer. Cold Spring Harb Symp Quant Biol
2005; 70: 187–96.
Clyne M. Prostate cancer: androgen deprivation causes EMT in the prostate. Nat Rev Urol
2011; 9: 4.
Kassi E, Moutsatsou P. Glucocorticoid receptor signaling and prostate cancer. Cancer Lett
2011; 302: 1–10.
Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, et al.
Prostate cancer. Lancet
2016; 387: 70–82.
Blute ML Jr, Damaschke NA, Jarrard DF. The epigenetics of prostate cancer diagnosis and prognosis: update on clinical applications. Curr Opin Urol
2015; 25: 83–8.
van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, et al.
Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell
1991; 65: 737–52.
Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, et al.
Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev
1999; 13: 2678–90.
Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature
1999; 397: 164–8.
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, et al.
The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev
2007; 21: 525–30.
Sahasrabuddhe AA. BMI1: a biomarker of hematologic malignancies. Biomark Cancer
2016; 8: 65–75.
van Leenders GJ, Dukers D, Hessels D, van den Kieboom SW, Hulsbergen CA, et al.
Polycomb-group oncogenes EZH2
, and RING1
are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol
2007; 52: 455–63.
Mills AA. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer
2010; 10: 669–82.
Papp B, Muller J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. Genes Dev
2006; 20: 2041–54.
Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol
2009; 10: 697–708.
Blackledge NP, Rose NR, Klose RJ. Targeting polycomb systems to regulate gene expression: modifications to a complex story. Nat Rev Mol Cell Biol
2015; 16: 643–9.
Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, et al.
Role of histone H2A ubiquitination in polycomb silencing. Nature
2004; 431: 873–8.
Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell
2005; 20: 845–54.
Raaphorst FM. Deregulated expression of polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet
2005; 14: R93–100.
Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, et al. Ink4a
differentially affect cell proliferation and neural stem cell self-renewal in Bmi1
-deficient mice. Genes Dev
2005; 19: 1438–43.
Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a
senescence pathways. Genes Dev
2005; 19: 1432–7.
Haupt Y, Bath ML, Harris AW, Adams JM. bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene
1993; 8: 3161–4.
Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M. Characterization and chromosomal localization of the human proto-oncogene BMI-1. Hum Mol Genet
1993; 2: 1597–603.
Yadav AK, Sahasrabuddhe AA, Dimri M, Bommi PV, Sainger R, et al.
Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain. Mol Cancer
2010; 9: 158.
Li Z, Cao R, Wang M, Myers MP, Zhang Y, et al.
Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. J Biol Chem
2006; 281: 20643–9.
Buchwald G, van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M, et al.
Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J
2006; 25: 2465–74.
So AY, Jung JW, Lee S, Kim HS, Kang KS. DNA methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS One
2011; 6: e19503.
Ginjala V, Nacerddine K, Kulkarni A, Oza J, Hill SJ, et al.
BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol Cell Biol
2011; 31: 1972–82.
Balasubramanian S, Scharadin TM, Han B, Xu W, Eckert RL. The Bmi-1 helix-turn and ring finger domains are required for Bmi-1 antagonism of (-) epigallocatechin-3-gallate suppression of skin cancer cell survival. Cell Signal
2015; 27: 1336–44.
Sanchez-Beato M, Sanchez E, Gonzalez-Carrero J, Morente M, Diez A, et al.
Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays. Mod Pathol
2006; 19: 684–94.
Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, et al.
Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol
2010; 12: 982–92.
Liu Y, Sanchez-Tillo E, Lu X, Huang L, Clem B, et al.
The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression. J Biol Chem
2014; 289: 4116–25.
Huang R, Cheung NK, Vider J, Cheung IY, Gerald WL, et al.
MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas. FASEB J
2011; 25: 4138–49.
Nowak K, Kerl K, Fehr D, Kramps C, Gessner C, et al. BMI1
is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res
2006; 34: 1745–54.
Wang HB, Liu GH, Zhang H, Xing S, Hu LJ, et al.
Sp1 and c-Myc regulate transcription of BMI1
in nasopharyngeal carcinoma. FEBS J
2013; 280: 2929–44.
Yang J, Chai L, Liu F, Fink LM, Lin P, et al. Bmi-1
is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci U S A
2007; 104: 10494–9.
Xie X, Piao L, Cavey GS, Old M, Teknos TN, et al.
Phosphorylation of Nanog is essential to regulate Bmi1 and promote tumorigenesis. Oncogene
2014; 33: 2040–52.
Yu T, Chen X, Zhang W, Colon D, Shi J, et al.
Regulation of the potential marker for intestinal cells, Bmi1, by beta-catenin and the zinc finger protein KLF4: implications for colon cancer. J Biol Chem
2012; 287: 3760–8.
Guo WJ, Datta S, Band V, Dimri GP. Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins. Mol Biol Cell
2007; 18: 536–46.
Bommi PV, Dimri M, Sahasrabuddhe AA, Khandekar J, Dimri GP. The polycomb group protein BMI1 is a transcriptional target of HDAC inhibitors. Cell Cycle
2010; 9: 2663–73.
Jin M, Zhang T, Liu C, Badeaux MA, Liu B, et al.
miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells. Cancer Res
2014; 74: 4183–95.
Yu J, Lu Y, Cui D, Li E, Zhu Y, et al.
miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol Rep
2014; 31: 910–8.
Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, et al.
Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell
2011; 20: 187–99.
Xuan H, Xue W, Pan J, Sha J, Dong B, et al.
Downregulation of miR-221, -30d, and -15a contributes to pathogenesis of prostate cancer by targeting Bmi-1. Biochemistry (Mosc)
2015; 80: 276–83.
Musumeci M, Coppola V, Addario A, Patrizii M, Maugeri-Sacca M, et al.
Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene
2011; 30: 4231–42.
Nacerddine K, Beaudry JB, Ginjala V, Westerman B, Mattiroli F, et al.
Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer. J Clin Invest
2012; 122: 1920–32.
Ismail IH, Gagne JP, Caron MC, McDonald D, Xu Z, et al.
CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic Acids Res
2012; 40: 5497–510.
Li Y, Wang L, Liu J, Zhang P, An M, et al.
O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer. Oncogene
2017; 36: 6293–305.
Lessard J, Sauvageau G. Bmi-1
determines the proliferative capacity of normal and leukaemic stem cells. Nature
2003; 423: 255–60.
Park IK, Qian D, Kiel M, Becker MW, Pihalja M, et al.
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature
2003; 423: 302–5.
Gialmanidis IP, Bravou V, Petrou I, Kourea H, Mathioudakis A, et al.
Expression of Bmi1, FoxF1, Nanog, and gamma-catenin in relation to hedgehog signaling pathway in human non-small-cell lung cancer. Lung
2013; 191: 511–21.
Wang X, Wang C, Zhang X, Hua R, Gan L, et al.
Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol
2016; 9: 90.
Song LB, Zeng MS, Liao WT, Zhang L, Mo HY, et al.
Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res
2006; 66: 6225–32.
Wang Y, Zhe H, Ding Z, Gao P, Zhang N, et al.
Cancer stem cell marker Bmi-1 expression is associated with basal-like phenotype and poor survival in breast cancer. World J Surg
2012; 36: 1189–94.
Wolters T, Vissers KJ, Bangma CH, Schroder FH, van Leenders GJ. The value of EZH2, p27(kip1), BMI-1 and MIB-1 on biopsy specimens with low-risk prostate cancer in selecting men with significant prostate cancer at prostatectomy. BJU Int
2010; 106: 280–6.
Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+
prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer
2008; 98: 756–65.
Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle
2005; 4: 1171–5.
Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest
2005; 115: 1503–21.
Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells
2012; 30: 372–8.
Siddique HR, Parray A, Zhong W, Karnes RJ, Bergstralh EJ, et al.
BMI1, stem cell factor acting as novel serum-biomarker for Caucasian and African-American prostate cancer. PLoS One
2013; 8: e52993.
van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, et al.
Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev
1994; 8: 757–69.
He S, Nakada D, Morrison SJ. Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol
2009; 25: 377–406.
Zencak D, Lingbeek M, Kostic C, Tekaya M, Tanger E, et al. Bmi1
loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci
2005; 25: 5774–83.
Brawer MK, Peehl DM, Stamey TA, Bostwick DG. Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res
1985; 45: 3663–7.
De Marzo AM, Meeker AK, Epstein JI, Coffey DS. Prostate stem cell compartments: expression of the cell cycle inhibitor p27Kip1
in normal, hyperplastic, and neoplastic cells. Am J Pathol
1998; 153: 911–9.
Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, et al.
p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol
2000; 157: 1769–75.
Draffin JE, McFarlane S, Hill A, Johnston PG, Waugh DJ. CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res
2004; 64: 5702–11.
Jaworska D, Krol W, Szliszka E. Prostate cancer stem cells: research advances. Int J Mol Sci
2015; 16: 27433–49.
Lukacs RU, Memarzadeh S, Wu H, Witte ON. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell
2010; 7: 682–93.
Yoo YA, Roh M, Naseem AF, Lysy B, Desouki MM, et al.
Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation. Nat Commun
2016; 7: 12943.
Koren A, Rijavec M, Kern I, Sodja E, Korosec P, et al. BMI1
, and CD133
transcripts connect epithelial-mesenchymal transition to cancer stem cells in lung carcinoma. Stem Cells Int
2016; 2016: 9714315.
Voncken JW, Schweizer D, Aagaard L, Sattler L, Jantsch MF, et al.
Chromatin-association of the polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J Cell Sci
1999; 112: 4627–39.
Ismail IH, Andrin C, McDonald D, Hendzel MJ. BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol
2010; 191: 45–60.
Holden JA. DNA topoisomerases as anticancer drug targets: from the laboratory to the clinic. Curr Med Chem Anticancer Agents
2001; 1: 1–25.
Alchanati I, Teicher C, Cohen G, Shemesh V, Barr HM, et al.
The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex – a potentially new drug target. PLoS One
2009; 4: e8104.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature
2001; 414: 105–11.
Hosen N, Yamane T, Muijtjens M, Pham K, Clarke MF, et al.
Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of bmi-1 expression in normal and leukemic hematopoietic cells. Stem Cells
2007; 25: 1635–44.
Dovey JS, Zacharek SJ, Kim CF, Lees JA. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci U S A
2008; 105: 11857–62.
Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, et al.
Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res
2006; 66: 6063–71.
Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, et al.
Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature
2004; 431: 707–12.
Sheng T, Li C, Zhang X, Chi S, He N, et al.
Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer
2004; 3: 29.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell
2009; 139: 871–90.
Mitra A, Mishra L, Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget
2015; 6: 10697–711.
Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol
2017; 14: 611–29.
Song LB, Li J, Liao WT, Feng Y, Yu CP, et al.
The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest
2009; 119: 3626–36.
Ren H, Du P, Ge Z, Jin Y, Ding D, et al.
TWIST1 and BMI1 in cancer metastasis and chemoresistance. J Cancer
2016; 7: 1074–80.
Ivanchuk SM, Mondal S, Dirks PB, Rutka JT. The Ink4a/Arf locus: role in cell cycle control and apoptosis and implications for glioma growth. J Neurooncol
2001; 51: 219–29.
Calao M, Sekyere EO, Cui HJ, Cheung BB, Thomas WD, et al.
Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation. Oncogene
2013; 32: 3616–26.
Su WJ, Fang JS, Cheng F, Liu C, Zhou F, et al.
RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development. Proc Natl Acad Sci U S A
2013; 110: 1720–5.
Crea F, Duhagon Serrat MA, Hurt EM, Thomas SB, Danesi R, et al.
BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer
2011; 128: 1946–54.
Chou DM, Adamson B, Dephoure NE, Tan X, Nottke AC, et al
. Achromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci U S A
2010; 107: 18475–80.
Fan C, He L, Kapoor A, Gillis A, Rybak AP, et al.
Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression. Biochim Biophys Acta
2008; 1782: 642–8.
Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin
2015; 36: 3–23.
Srinivas-Shankar U, Wu FC. Drug insight: testosterone preparations. Nat Clin Pract Urol
2006; 3: 653–65.
Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, et al.
Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res
2013; 73: 483–9.
Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev
2004; 25: 276–308.
Silva Neto B, Koff WJ, Biolchi V, Brenner C, Biolo KD, et al.
Polymorphic CAG and GGC repeat lengths in the androgen receptor gene and prostate cancer risk: analysis of a Brazilian population. Cancer Invest
2008; 26: 74–80.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, et al.
AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med
2014; 371: 1028–38.
Bohrer LR, Chen S, Hallstrom TC, Huang H. Androgens suppress EZH2 expression via retinoblastoma (RB) and p130-dependent pathways: a potential mechanism of androgen-refractory progression of prostate cancer. Endocrinology
2010; 151: 5136–45.
Zhu S, Zhao D, Yan L, Jiang W, Kim JS, et al.
BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1. Nat Commun
2018; 9: 500.
Ismail IH, McDonald D, Strickfaden H, Xu Z, Hendzel MJ. A small molecule inhibitor of polycomb repressive complex 1 inhibits ubiquitin signaling at DNA double-strand breaks. J Biol Chem
2013; 288: 26944–54.
Ohtaka M, Itoh M, Tohda S. BMI1 inhibitors down-regulate NOTCH signaling and suppress proliferation of acute leukemia cells. Anticancer Res
2017; 37: 6047–53.
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, et al.
Self-renewal as a therapeutic target in human colorectal cancer. Nat Med
2014; 20: 29–36.
Mayr C, Wagner A, Loeffelberger M, Bruckner D, Jakab M, et al.
The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells. Oncotarget
2016; 7: 745–58.
Jalal S, Earley JN, Turchi JJ. DNA repair: from genome maintenance to biomarker and therapeutic target. Clin Cancer Res
2011; 17: 6973–84.
Yong KJ, Basseres DS, Welner RS, Zhang WC, Yang H, et al.
Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPalpha expression. Sci Transl Med
2016; 8: 350ra104.
Bolomsky A, Schlangen K, Schreiner W, Zojer N, Ludwig H. Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment. J Hematol Oncol
2016; 9: 17.
Cao L, Bombard J, Cintron K, Sheedy J, Weetall ML, et al.
BMI1 as a novel target for drug discovery in cancer. J Cell Biochem
2011; 112: 2729–41.
Bansal N, Bartucci M, Yusuff S, Davis S, Flaherty K, et al.
BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer. Clin Cancer Res
2016; 22: 6176–91.
Infante JR, Bedard PL, Shapiro G, Bauer TM, Prawira A, et al.
Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein. J Clini Oncol
2017; 35: 2574.
Nishida Y, Maeda A, Kim MJ, Cao L, Kubota Y, et al.
The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells. Blood Cancer J
2017; 7: e527.
Palumbo T, Faucz FR, Azevedo M, Xekouki P, Iliopoulos D, et al.
Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene
2013; 32: 1651–9.
Venkataraman S, Alimova I, Fan R, Harris P, Foreman N, et al.
MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastoma cancer cell growth by promoting senescence. PLoS One
2010; 5: e10748.
Zhu G, Wang Y, Mijiti M, Wang Z, Wu PF, et al.
Upregulation of miR-130b enhances stem cell-like phenotype in glioblastoma by inactivating the Hippo signaling pathway. Biochem Biophys Res Commun
2015; 465: 194–9.
Qi X, Li J, Zhou C, Lv C, Tian M. MicroRNA-320a inhibits cell proliferation, migration and invasion by targeting BMI-1 in nasopharyngeal carcinoma. FEBS Lett
2014; 588: 3732–8.
Chen T, Xu C, Chen J, Ding C, Xu Z, et al.
MicroRNA-203 inhibits cellular proliferation and invasion by targeting Bmi1 in non-small cell lung cancer. Oncol Lett
2015; 9: 2639–46.
He Z, Xia Y, Pan C, Ma T, Liu B, et al.
Up-regulation of miR-452 inhibits metastasis of non-small cell lung cancer by regulating BMI1. Cell Physiol Biochem
2015; 37: 387–98.
Xi S, Xu H, Shan J, Tao Y, Hong JA, et al.
Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis. J Clin Invest
2013; 123: 1241–61.
Wu C, Zheng X, Li X, Fesler A, Hu W, et al.
Reduction of gastric cancer proliferation and invasion by miR-15a mediated suppression of Bmi-1 translation. Oncotarget
2016; 7: 14522–36.
Cho JH, Dimri M, Dimri GP. MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence. J Biol Chem
2015; 290: 10555–67.
Kopp F, Oak PS, Wagner E, Roidl A. miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression. PLoS One
2012; 7: e50469.
Wang L, Liu JL, Yu L, Liu XX, Wu HM, et al.
Downregulated miR-495 [Corrected] Inhibits the G1-S phase transition by targeting Bmi-1 in breast cancer. Medicine (Baltimore)
2015; 94: e718.
Gong XF, Yu AL, Tang J, Wang CL, He JR, et al.
MicroRNA-630 inhibits breast cancer progression by directly targeting BMI1. Exp Cell Res
2017; 362: 378–85.
Jones MF, Hara T, Francis P, Li XL, Bilke S, et al.
The CDX1-microRNA-215 axis regulates colorectal cancer stem cell differentiation. Proc Natl Acad Sci U S A
2015; 112: E1550–8.
He X, Dong Y, Wu CW, Zhao Z, Ng SS, et al.
MicroRNA-218 inhibits cell cycle progression and promotes apoptosis in colon cancer by downregulating BMI1 polycomb ring finger oncogene. Mol Med
2013; 18: 1491–8.
Teshima K, Nara M, Watanabe A, Ito M, Ikeda S, et al.
Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma. Oncogene
2014; 33: 2191–203.
Wei Y, Du Y, Chen X, Li P, Wang Y, et al.
Expression patterns of microRNA-218 and its potential functions by targeting CIP2A and BMI1 genes in melanoma. Tumour Biol
2014; 35: 8007–15.
Chang X, Sun Y, Han S, Zhu W, Zhang H, et al.
MiR-203 inhibits melanoma invasive and proliferative abilities by targeting the polycomb group gene BMI1. Biochem Biophys Res Commun
2015; 456: 361–6.
Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, et al.
MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1. J Biol Chem
2005; 280: 5178–87.
Sahasrabuddhe AA, Dimri M, Bommi PV, Dimri GP. βTrCP regulates BMI1 protein turnover via ubiquitination and degradation. Cell Cycle
2011; 10: 1322–30.
[Figure 1], [Figure 2]