MUC1-C activates BMI1 in human cancer cells

Oncogene. 2017 May 18;36(20):2791-2801. doi: 10.1038/onc.2016.439. Epub 2016 Nov 28.

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-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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mucin-1 / chemistry
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • NF-kappa B / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Polycomb Repressive Complex 1 / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proto-Oncogene Proteins c-myc / metabolism
  • Transcription, Genetic
  • Ubiquitination

Substances

  • BMI1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Homeodomain Proteins
  • Mucin-1
  • NF-kappa B
  • Proto-Oncogene Proteins c-myc
  • Polycomb Repressive Complex 1