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.

Keywords: Bmi-1; cancer therapy; chemoresistance; miRNAs; molecular mechanism; tumorigenesis.

Figure 1

The structure of gene and protein of Bmi-1. The Bmi-1 gene contains 10 exons and 9 introns. The amino acid sequence of Bmi-1 protein contains a RING finger domain, a helix–turn–helix, two nuclear localization signals (NLS), and a PEST region.

Figure 2

Downstream genes directly regulated by Bmi-1. Bmi-1 can enhance H2A ubiquitination and bind to the promoter of HoxC13 to reduce the expression of HoxC13 in HeLa cells [77]. The most classic downstream target of Bmi-1 is INK4a/ARF. The tumor suppressor gene INK4a/ARF can encode two regulatory genes: p16^INK4a and p14^ARF (p19^ARF in mice). P16^INK4a arrests cells in G0/G1 phase through cyclinD-CDK4/6-pRb-E2F. p14^ARF regulates the cell apoptosis through MDM2-p53 pathway [76]. Bmi-1 can regulate the development of colon cancer by negatively regulating the expression level of PTEN and then activating the Akt/GSK3β axis [78]. Bmi-1 regulates memory CD4 T cell survival via repression of the proapoptotic BH3-only protein Noxa gene [80]. Bmi-1 regulates cell fate via transcriptional repression tumor suppressor WW Domain Containing Oxidoreductase (WWOX) in small-cell lung cancer cells [81]. Bmi-1 suppresses the expression of Smgc gene and Gcnt3 gene [82]. Bmi-1 activates Wnt signaling in colon cancer by negatively regulating the Wnt antagonist IDAX [83]. Bmi-1 can also transcriptionally positively regulate human telomerase reverse transcriptase (hTERT) to block senescence in human mammary epithelial cells [79].