BMI1 In Cancer Cells Research Articles

A miR-200c/141-BMI1 autoregulatory loop regulates oncogenic activity of BMI1 in cancer cells.

MicroRNAs (miRNAs) are known to function as oncomiRs or tumor suppressors and are important noncoding RNA regulators of oncogenesis. The miR-200c/141 locus on chromosome 12 encodes miR-200c and miR-141, two members of the miR-200 family, which have been shown to function as tumor suppressive miRNAs by targeting multiple oncogenic factors such as polycomb group protein BMI1. Here, we show that BMI1 reciprocally functions as a transcriptional repressor of the miR-200c/141 cluster and that BMI1 inhibitors upregulate expression of miR-200c and miR-141. Our data suggest that BMI1 binds to the miR-200c/141 promoter and regulates it through transcription factor binding motifs E-box 2 and Z-box 1 to repress expression of miR-200c/141 cluster. We also show that PTC-209, a small molecule inhibitor of BMI1 gene expression induces cellular senescence and transcriptionally upregulates expression of miR-200c/141 cluster in breast cancer cells. Furthermore, inhibition of expression of miR-200c or miR-141 overcomes tumor suppressive effects of PTC-209 including induction of cellular senescence and downregulation of breast cancer stem cell phenotype. Therefore, our studies suggest a reciprocal regulation between BMI1 and miR-200c/141 cluster, and that BMI1 inhibitory drugs can further amplify their inhibitory effects on BMI1 via multiple mechanisms including posttranscriptional regulation by upregulating BMI1 targeting miRNAs.

TWIST1 and BMI1 in Cancer Metastasis and Chemoresistance.

Purpose Increasing evidences revealed that cancer cells with the characteristics of epithelial-mesenchymal transition (EMT) or cancer stem cells (CSC) have high ability of progression, invasion, metastasis and chemoresistance. TWIST1 and BMI1 are crucial transcription factors required for EMT and CSC. Both TWIST1 and BMI1 are up-regulated in various cancers and have a positive correlation with poor prognosis. Although recent results showed that the two molecules function in promoting cancer metastasis and chemoresistance respectively, the correlation of TWIST1 and BMI1 is not well understood.Methods In this review, we summarize recent advance in cancer research focus on TWIST1 and BMI1 in cancer metastasis and chemoresistance, and emphasize the possible link between EMT and CSC.Results Further investigation of TWIST1 and BMI1 cooperately promote CSC proliferation due to EMT-associated effect will help to understand the mechanism of tumor cells metastasis and chemoresistance.Conclusions TWIST1 and BMI1 in cancer cells will be effective targets for treating chemoresistant metastatic lesions.

Negative regulation of Bmi-1 by AMPK and implication in cancer progression.

Bmi-1 is a transcriptional regulator that promotes tumor cell self-renewal and epithelial to mesenchymal transition and its upregulation is associated with tumor progression, AMPK is an intracellular fuel-sensing enzyme and plays important roles in tumor cell growth and progression. Thus, the present study aims to examine the regulation of Bmi-1 by AMPK. First, our data revealed that, as compared to adjacent normal tissue, Bmi-1 was highly expressed in gastric cancer, whereas phosphorylation of AMPK (p-AMPK) was reduced. Similar findings were observed in lung adenocarcinomas and appeared that the expression of Bmi-1 was correlated with pathological grades of the cancer, where opposite changes were found in p-AMPK. Second, Metformin, a pharmacological AMPK activator and anti-diabetic drug, or ectopic expression of LKB1, diminished expression of Bmi-1 in cancer cells, an event that was reversed by silencing LKB1. Third, knockdown of LITAF, previously identified as a downstream target of AMPK, upregulated Bmi-1, associated with increased cell viability, colony formation, and migration of cancer cells in vitro. Fourth, metformin increased the abundance of miR-15a, miR-128, miR-192, and miR-194, which was prevented by knockdown of LITAF. Accordingly, transfection of these individual miRNAs downregulated Bmi-1. Altogether, our data for the first time suggest a regulatory axis in cancer cells: AMPK upregulates LITAF, which in turn increases miRNAs, leading to attenuation of Bmi-1 expression.

Abstract 4158: MicroRNA-mediated regulation of Bmi1 expression in gastric and colon cancer cells.

Abstract Background: MicroRNAs (miRs) target the 3’-untranslated region (3’-UTR) of mRNA and induce translational suppression or mRNA degradation. Bmi1 is a member of the polycomb-repressive complex 1 (PRC1) that has an essential role in maintaining chromatin silencing, and is involved in the self-renewal of neuronal, haematopoietic and intestinal cells through repression of the INK4A-ARF locus. The regulatory mechanism of Bmi1 in cancer cells is still unknown. The aim of this study is to clarify the miR-mediated regulatory mechanism of Bmi1 expression in gastric and colon cancer cells. Methods and Results: We searched for miRNAs that might regulate Bmi1 using miRBase and selected 64 miRNAs as a candidate. In these miRNAs, we focused miR-30e-3p that was known to be down-regulated in colon, breast and esophageal cancer cells. First, we examined the expression of miR-30e-3p in matched cancer tissue and non-tumor tissue using formalin-fixed paraffin-embedded(FFPE) samples of gastric and colon cancer. We confirmed the expression of miR-30e-3p was significantly lower in cancer tissue than in non-tumor tissue. Next, we measured the expression of miR-30e-3p and Bmi1 by real time PCR and western blotting using gastric and colon cancer cell lines. The endogenous expression of Bmi1 and miR-30e-3p showed inverse correlation in each cell lines. Then we examined the effect of overexpression or down regulation of miR-30e-3p on the expression of Bmi1. The suppression of miR-30e-3p increased Bmi1 expression, and the overexpression of miR-30e-3p decreased Bmi1 expression. Conclusion: Our current study revealed that the expression of Bmi1 was affected by miR-30e-3p in gastric and colon cancer. Mir-30e-3p may be a therapeutic target for the treatment of gastric and colon cancer. Citation Format: Hidetaka Sugihara, Takatsugu Ishimoto, Masayuki Watanabe, Hideo Baba. MicroRNA-mediated regulation of Bmi1 expression in gastric and colon cancer cells. [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 4158. doi:10.1158/1538-7445.AM2013-4158