BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling
Hifzur Rahman Siddique, Aijaz Parray, Rohinton S Tarapore, Lei Wang, Hasan Mukhtar, R Jeffery Karnes, Yibin Deng, Badrinath R Konety, Mohammad Saleem, Hifzur Rahman Siddique, Aijaz Parray, Rohinton S Tarapore, Lei Wang, Hasan Mukhtar, R Jeffery Karnes, Yibin Deng, Badrinath R Konety, Mohammad Saleem
Abstract
For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Siegel R, Naishadham D, Jemal A (2012) Cancer Statistics. CA Cancer J Clin 62: 10–29.
- Jemal A, Siegel R, Hao Y, Xu J, Thun MJ (2010) Cancer statistics CA Cancer. J Clin 60: 277–300.
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90.
- Mahon KL, Henshall SM, Sutherland RL, Horvath LG (2011) Pathways of chemotherapy resistance in castration-resistant prostate cancer. Endocr Relat Cancer 18: R103–123.
- Zhang L, Jiao M, Li L, Wu D, Wu K, et al. (2012) Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties. J Cancer Res Clin Oncol 138: 675–686.
- Kotb AF, Elabbady AA (2011) Prognostic factors for the development of biochemical recurrence after radical prostatectomy. Prostate Cancer 2011: 485189.
- Parray A, Siddique HR, Nanda S, Konety BR, Saleem M (2012) Castration-resistant prostate cancer: potential targets and therapies. Biologics 6: 267–276.
- Catalona WJ, Smith DS (1998) Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol 160: 2428.
- Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, et al. (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591–1597.
- Han M, Partin AW, Zahurak M, Piantadosa S, Epstein JI, et al. (2003) Biochemical (Prostate Specific Antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 169: 517–523.
- Siddique HR, Saleem M (2012) Role of BMI1, a Stem Cell Factor in Cancer Recurrence and Chemoresistance: Preclinical and Clinical Evidences. Stem Cells 30: 372–378.
- Kang MK, Kim RH, Kim SJ, Yip FK, Shin KH, et al. (2007) Elevated BMI1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br J Cancer 96: 126–133.
- Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, et al. (1999) BMI1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 13: 2678–2690.
- Cui H, Hu B, Li T, Ma J, Alam G, et al. (2007) BMI1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 170: 1370–1378.
- Wang E, Bhattacharyya S, Szabolcs A, Rodriguez-Aguayo C, Jennings NB, et al. (2011) Enhancing chemotherapy response with BMI1 silencing in ovarian cancer. PLoS One 6: e17918.
- Huber GF, Albinger-Hegyi A, Soltermann A, Roessle M, Graf N, et al. (2011) Expression patterns of BMI1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma. Cancer 117: 4659–4670.
- Glinsky GV, Berezovska O, Glinskii AB (2005) Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 115: 1503–1521.
- Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, et al. (1997) Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 3: 402–408.
- Siddique HR, Mishra SK, Karnes RJ, Saleem M (2011) Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy. Clin Cancer Res 17: 5379–5391.
- Siddique HR, Liao DJ, Mishra SK, Schuster T, Wang L, et al. (2012) Epicatechin-rich cocoa polyphenol inhibits kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. Int J Cancer 131: 1720–1731.
- Saleem M, Adhami VM, Zhong W, Longley BJ, Lin CY, et al. (2006) A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1. Cancer Epidemiol Biomarkers Prev 15: 217–227.
- O'Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, et al. (2011) Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer 10: 126.
- Siddique HR, Parray A, Zhong W, Karnes JR, Bergstralh EJ, et al. (2013) BMI1, Stem Cell Factor Acting as Novel Serum-biomarker for Caucasian and African-American Prostate Cancer. PLOS ONE 8: e52993.
- Hegde GV, Munger CM, Emanuel K, Joshi AD, Greiner TC, et al. (2008) Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma. Mol Cancer Ther 7: 1450–1460.
- Rohrs S, Kutzner N, Vlad A, Grunwald T, Ziegler S, et al. (2009) Chronological expression of Wnt target genes Ccnd1, Myc, Cdkn1a, Tfrc, Plf1 and Ramp3. Cell Biol Int 33: 501–508.
- Kanwar SS, Yu Y, Nautiyal J, Patel BB, Majumdar AP (2010) The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer 9: 212.
- Bigelow RL, Chari NS, Unden AB, Spurgers KB, Lee S, et al. (2004) Transcriptional regulation of BCL2 mediated by the sonic hedgehog signaling pathway through Gli-1. J Biol Chem 279: 1197–1205.
- Schug J (2008) Using TESS to predict transcription factor binding sites in DNA sequence. Curr Protoc Bioinformatics. Chapter 2: Unit 2.6 doi: .
- Song LB, Li J, Liao WT, Feng Y, Yu CP, et al. (2009) The polycomb group protein BMI1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest 119: 3626–3636.
- Crea F, Duhagon Serrat MA, Hurt EM, Thomas SB, Danesi R, et al. (2011) BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. Int J Cancer 128: 1946–1954.
- Siddique HR, Nanda S, Parray A, Saleem M (2012) Androgen receptor in human health: a potential therapeutic target. Curr Drug Targets 13: 1907–16.
- Casimiro M, Rodriguez O, Pootrakul L, Aventian M, Lushina N, et al. (2007) ErbB-2 induces the cyclin D1 gene in prostate epithelial cells in vitro and in vivo. Cancer Res 67: 4364–4372.
- Kang MH, Reynolds CP (2009) BCL2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15: 1126–1132.
- Brunelle JK, Letai A (2009) Control of mitochondrial apoptosis by the BCL2 family. J Cell Sci 122 (Pt 4) 437–441.
- Mackler NJ, Pienta KJ (2005) Drug insight: use of docetaxel in prostate and urothelial cancers. Nat Clin Pract Urol 2: 92–100.
- Straten P, Andersen MH (2010) The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens. Oncotarget 1: 239–245.
- Mahindroo N, Punchihewa C, Fujii N (2009) Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J Med Chem 52: 3829–3845.
- Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, et al. (2006) Hedgehog signaling and BMI1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66: 6063–6071.
- Petrylak DP (2007) New paradigms for advanced prostate cancer. Rev Urol 9 Suppl 2: S3–S12.
- Ross RW, Beer TM, Jacobus S, Bubley GJ, Taplin ME, et al. (2008) Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer 112: 521–6.
- Sánchez C, Mercado A, Contreras HR, Mendoza P, Cabezas J, et al. (2011) Chemotherapy sensitivity recovery of prostate cancer cells by functional inhibition and knock down of multidrug resistance proteins. Prostate 71: 1810–7.
- Chen KG, Sikic BI (2012) Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res 18: 1863–9.
Source: PubMed