BMI1 as a novel target for drug discovery in cancer

Abstract

Growing evidence has demonstrated that clonogenic cancer stem (initiating) cells are responsible for tumor regrowth and disease relapse. Bmi-1 plays a critical role in the self-renewal of adult stem cells. The Bmi-1 protein is elevated in many types of cancers, and experimental reduction of Bmi-1 protein levels by small interfering RNA (siRNA) causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. The Bmi-1 protein has no known enzymatic activity, but serves as the key regulatory component of the PRC1 complex (polycomb repressive complex-1). This complex influences chromatin structure and regulates transcriptional activity of a number of important loci including the Ink4a locus which encodes the tumor suppressor proteins p16(Ink4a) and p14(Arf) . In this prospective study, we will discuss the implication of BMI1 in cancers, the biology of BMI1, and the regulatory control of BMI1 expression. The target validation and the future prospects of targeting BMI1 in cancer therapy are also discussed.

Association of BMI-1 and p16 as prognostic factors for head and neck carcinomas

“…BMI-1 is a member of a family of transcriptional repressors [15] and a known upstream modulator of p16 [16]. BMI-1's effect on p16 expression is of interest as p16 is widely in clinical use as a surrogate marker of HPV infection in OPSCC [3].…”

“…This contradiction could be explained by the fact that, in addition to its repressive effect on tumor suppressor p16, BMI-1 acts also via numerous other pathways independent of p16. It has also been suggested that BMI-1 alone should not be sufficient for tumor progression [8,16].…”

Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

“…While debate continues as to the precise identity and function of CSCs, there is common agreement that CSCs show increased chemoresistance and radioresistance. (140)(141)(142)145) Therefore, understanding the biology of chemoresistance potential of CSCs may contribute to our understanding of tumor biology and would have far-reaching clinical implications.…”

“…(146) BMI1 is reported to play a crucial role in self-renewal of stem cells and is associated with a number of human malignancies. (141,144,(147)(148)(149) Recent studies suggest that BMI1 is involved in the initiation of cancer, and targeting BMI1 by gene therapy abolishes chemoresistance in tumor cells. (141,142) The inability of tumor cells to go through apoptosis in response to chemotherapy gives a selective advantage for tumor progression, metastasis, and resistance to therapy.…”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…It is uniquely expressed by the rapidly cycling stem cells, but is dispensable for Lgr5 stem cell self-renewal and differentiation [24]. Bmi1 is a member of the Polycomb Repressive Complex 1 (PRC1); it is expressed in stem cells in several tissues [25] and within the gut it is expressed in the quiescent +4 stem cells.…”