MUC1-C activates BMI1 in human cancer cells

M. Hiraki, T. Maeda, A. Bouillez, M. Alam, A. Tagde, K. Hinohara, Y. Suzuki, T. Markert, M. Miyo, K. Komura, R. Ahmad, H. Rajabi, D. Kufe

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (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-Câ †'ï 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 p16 INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16 INK4a expression. In support of these results, analysis of three gene expresssion data sets 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.

Original languageEnglish
Pages (from-to)2791-2801
Number of pages11
JournalOncogene
Volume36
Issue number20
DOIs
Publication statusPublished - May 18 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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