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

Abstract

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.

Knockdown of BMI1 is sensitive to Paclitaxel in cervical and endometrial cancer

“…The BMI1 inhibitor, from rst-generation PTC-209 to second-generation PTC-028, shows potential effects on the inhibition of cancer cell viability [11; 12]. Although the roles of several key inhibitors have been comprehensively summarized in different tumor cell models, only one inhibitor has been tested in CC and EC respectively [23]. Notably, PTC-596 is the only one BMI1 inhibitor now in the clinical phase 1 trial of diffuse intrinsic pontine glioma and leiomyosarcoma [24; 25], but there is a lack of a unique drug to be used in clinical practice to target BMI1 speci cally.…”

The role and prospect of lysine‐specific demethylases in cancer chemoresistance

“…Mechanically, KDM1A could up‐regulate stemness markers Sox2 and Oct4 or suppress negative regulators of β‐catenin signaling 96,97,99 . In HNSCC cancer cells, KDM1A overexpression confers CSC‐like characteristics through enhancing the expression of Bmi‐1, 142 a promoter of tumor metastasis and chemoresistance 144 . In HCC cancer cells, CD13 is a new marker in liver CSCs that promotes sorafenib resistance in HCC.…”

“…96,97,99 In HNSCC cancer cells, KDM1A overexpression confers CSC-like characteristics through enhancing the expression of Bmi-1, 142 a promoter of tumor metastasis and chemoresistance. 144 In HCC cancer cells, CD13 is a new marker in liver CSCs that promotes sorafenib resistance in HCC. CD13 interacts with histone deacetylase5 (HDAC5) to promote protein stability, activating nuclear factor kappa B signaling via KDM1A demethylation of p65.…”

Discovery and SAR Studies of Potent Modulators of BMI‐1 Expression

“…[3] BMI1 Expression is regulated by various mechanisms, including transcriptional, post-transcriptional and post-translational regulation. [4,5] Transcriptional regulation of BMI1 expression involves binding of the transcription factors to the promoter region of the BMI1 gene, which can activate or repress its transcription. Post-transcriptional regulation of BMI1 expression involves various processes that control mRNA stability and translational efficiency.…”

“…Collectively, these observations establish BMI1 as a promising target for oncology drug development. [4,5] As BMI1 is nonenzymatic, targeting this protein by traditional drug discovery methods represents a challenge and has yet to be achieved. [10] Small molecule drugs that reduce BMI1 protein levels may provide longer lasting therapeutic benefit when added to the existing therapeutic regimens.…”