MUC1-C activates BMI1 in human cancer cells

Abstract

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.

MUC1-C Oncoprotein Integrates a Program of EMT, Epigenetic Reprogramming and Immune Evasion in Human Carcinomas

“…BMI1 has also been linked with self-renewal of cancer stem-like cells, and the induction of EMT and invasive tumor phenotypes [41]. Intriguingly, targeting MUC1-C in human carcinoma cells results in the suppression of BMI1, RING1 and RING2, indicating that MUC1-C promotes the expression of multiple PRC1 subunits [42]. With regard to the mechanistic regulation of BMI1, the evidence indicates that MUC1-C activates the BMI1 promoter by a MYC-dependent mechanism [42].…”

“…Intriguingly, targeting MUC1-C in human carcinoma cells results in the suppression of BMI1, RING1 and RING2, indicating that MUC1-C promotes the expression of multiple PRC1 subunits [42]. With regard to the mechanistic regulation of BMI1, the evidence indicates that MUC1-C activates the BMI1 promoter by a MYC-dependent mechanism [42]. MUC1-C also blocks miR-200c-mediated downregulation of BMI1 expression, linking this mechanism to ZEB1-induced suppression of miR-200c and the EMT program [42].…”

“…With regard to the mechanistic regulation of BMI1, the evidence indicates that MUC1-C activates the BMI1 promoter by a MYC-dependent mechanism [42]. MUC1-C also blocks miR-200c-mediated downregulation of BMI1 expression, linking this mechanism to ZEB1-induced suppression of miR-200c and the EMT program [42]. Analysis of gene expression datasets further demonstrated highly significant correlations between MUC1-C and BMI1, supporting the notion that MUC1-C contributes to the overexpression of BMI1 in breast and other carcinomas [42].…”

“…MUC1-C also blocks miR-200c-mediated downregulation of BMI1 expression, linking this mechanism to ZEB1-induced suppression of miR-200c and the EMT program [42]. Analysis of gene expression datasets further demonstrated highly significant correlations between MUC1-C and BMI1, supporting the notion that MUC1-C contributes to the overexpression of BMI1 in breast and other carcinomas [42]. MUC1-C also directs BMI1 function by binding directly to this stem cell factor, promoting occupancy of BMI1 on the CDKN2A promoter and repressing expression of the p16 INK4a tumor suppressor [42].…”

Microrna-452 Exerts Growth-Suppressive Activity against T-Cell Acute Lymphoblastic Leukemia

“…Among them, BMI1 had attracted more attention because it is a well-defined oncogene 17. Moreover, a previous study has reported that miR-452 can regulate BMI1 expression in NSCLC 12.…”