Journal Article

BMI1 Polycomb Group Protein Acts as a Master Switch for Growth and Death of Tumor Cells: Regulates TCF4-Transcriptional Factor-Induced BCL2 Signaling

Parray, Aijaz, Saleem, Mohammad, Siddique, Hifzur Rahman, Deng, Yibin, Konety, Badrinath R., Wang, Lei, Karnes, R. Jeffery, Mukhtar, Hasan, Tarapore, Rohinton S.

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal models / Animals / Antineoplastic Agents - pharmacology / Apoptosis / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism / Binding sites / Biology / Cancer / Cancer therapies / Cell cycle / Cell growth / Cell Proliferation - drug effects / Cellular Senescence / Chemoresistance / Chemotherapy / Cisplatin - pharmacology / Colorectal cancer / Dermatology / Development and progression / Disease control / DNA microarrays / Drug Resistance, Neoplasm / Gene Expression Regulation, Neoplastic / Genes / Genetic aspects / HT29 Cells / Humans / Laboratories / Luciferase / Male / Medical prognosis / Medicine / Metastasis / Metribolone - pharmacology / Mice / Mice, Nude / Neoplasm Transplantation / Plasmids / Polycomb group proteins / Polycomb Repressive Complex 1 - physiology / Promoter Regions, Genetic / Prostate - metabolism / Prostate cancer / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Protein Binding / Proteins / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / Signal Transduction / Signaling / Stem cell factor / Stem cells / Taxoids - pharmacology / Testosterone Congeners - pharmacology / Tissues / Transcription (Genetics) / Transcription Factor 4 / Transcription Factors - metabolism / Tumor cells / Tumors / Urology