BMI1 In Cancer Research Articles

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies.

B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.

Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy.

Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinico-pathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied. Therefore, in the present study we investigated the potential therapeutic benefit of radiation therapy in BMI1-silenced breast cancer cells and studied the mechanism(s) of radiosensitization. Human MDA-MB-231 and SUM159PT breast cancer cells that were either stably transfected with a lentiviral vector expressing BMI1 shRNA (shBMI1) or control shRNA (shControl) or transient transfection with a BMI1-specific siRNA were used. Silencing of BMI1 resulted in marked reduction in BMI1 both at the mRNA and protein level that was accompanied by a significant reduction in cell migration compared to control cells. Further, BMI1 knockdown produced a marked enhancement of DNA damage as evidenced by Comet Assay and γH2AX foci, resulting in a dose-dependent radiosensitization effect. Molecular studies revealed modulation of protein expression that is associated with the DNA damage response (DDR) and autophagy pathways. Our results demonstrate that BMI1 is an important therapeutic target in breast cancer and suppression of BMI1 produces radiation sensitivity. Further, combining BMI1-targeted therapeutics with radiation might benefit patients diagnosed with TNBC.

MUC1-C activates BMI1 in human cancer cells.

BMI1 is a component of the PRC1 complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion datasets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.

BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization.

BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and emerging data support a role of BMI1 in cancer. The central domain of BMI1 is involved in protein–protein interactions and is essential for its oncogenic activity. Here, we present the structure of BMI1 bound to the polyhomeotic protein PHC2 illustrating that the central domain of BMI1 adopts an ubiquitin-like (UBL) fold and binds PHC2 in a β-hairpin conformation. Unexpectedly, we find that the UBL domain is involved in homo-oligomerization of BMI1. We demonstrate that both the interaction of BMI1 with polyhomeotic proteins and homo-oligomerization via UBL domain are necessary for H2A ubiquitination activity of PRC1 and for clonogenic potential of U2OS cells. Here, we also emphasize need for joint application of NMR spectroscopy and X-ray crystallography to determine the overall structure of the BMI1–PHC2 complex.

Abstract 1794: Cross-regulation of polycomb group protein BMI1 and WNT inhibitors.

Abstract Polycomb group (PcG) proteins are evolutionarily conserved gene silencers, which determine cell fate decisions during development. These proteins are often aberrantly expressed in cancer cells. In particular, BMI1 and EZH2 are known to be overexpressed in a number of human malignancies including breast and prostate cancers. In vitro models of cancer development strongly support oncogenic role of overexpressed BMI1 in cancer and metastasis. BMI1 is known to be required for self-renewal of neural, hematopoietic, intestinal and mammary stem cells. In addition, BMI1 is downregulated in senescent cells, and this downregulation may contribute to age-related pathologies. BMI1 is also suspected to play a role in cancer stem cell development and increase stem cell-ness of tumors to promote drug resistance. Despite its role in cancer, stem cell phenotype, development and aging, very little is known about the signaling pathways that regulate the expression of BMI1. Here we report that BMI1 activates WNT pathway and upregulates its target genes such as Cyclin D1 and c-Myc. Using promoter-reporter assays, quantitative RT-PCR and Western blot analyses, we show that BMI1 auto-activates its expression via an E-box present in its promoter. Because auto-activation of BMI1 depends on E-box sequences present in its promoter, we hypothesized that BMI1 may regulate expression of c-Myc directly or indirectly via activation of WNT pathway. Indeed, our data suggest that BMI1 upregulated expression of c-Myc via activation of WNT pathway. Further dissection of this regulation revealed that BMI1 represses expression of WNT inhibitors, in particular DKK family of proteins such as DKK1, DKK2 and DKK3. Interestingly, we also found that DKK1 inhibits expression of BMI1, which also depends on E-box present in BMI1 promoter. Thus BMI1 and WNT inhibitors such as DKK1 cross-regulate each other's expression. We speculate that such regulation might favor BMI1 overexpression in cancer cells via increased WNT activity and c-Myc expression. On the other hand, increased expression of WNT inhibitors such as DKK1 might favor BMI1 downregulation in senescent and aged tissues. Thus, a fine tuned positive feedback loop controls BMI1 expression via WNT signaling pathway, and this feedback loop may be relevant to the role of BMI1 in cancer, stem cells and senescence. Citation Format: Joon-Ho Cho, Manjari Dimri, Goberdhan P. Dimri. Cross-regulation of polycomb group protein BMI1 and WNT inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1794. doi:10.1158/1538-7445.AM2013-1794

BMI1 as a novel target for drug discovery in cancer

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.

MiR-15a and MiR-16 Control Bmi-1 Expression in Ovarian Cancer

Oncogenic activation of Bmi-1 is found in a wide variety of epithelial malignancies including ovarian cancer, yet a specific mechanism for overexpression of Bmi-1 has not been determined. Thus, realizing the immense pathologic significance of Bmi-1 in cancer, we wanted to investigate if microRNA (miRNA) aberrations played a role in the regulation of Bmi-1 in ovarian cancer. In this report, we identify two miRNAs, miR-15a and miR-16, that are underexpressed in ovarian cell lines and in primary ovarian tissues. We show that these miRNAs directly target the Bmi-1 3' untranslated region and significantly correlate with Bmi-1 protein levels in ovarian cancer patients and cell lines. Furthermore, Bmi-1 protein levels are downregulated in response to miR-15a or miR-16 expression and lead to significant reduction in ovarian cancer cell proliferation and clonal growth. These findings suggest the development of therapeutic strategies by restoring miR-15a and miR-16 expression in ovarian cancer and in other cancers that involve upregulation of Bmi-1.