Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors

Elizabeth S. McKenna, Pablo Tamayo, Yoon Jae Cho, Erik J. Tillman, E. Lorena Mora-Blanco, Courtney G. Sansam, Edward C. Koellhoffer, Scott L. Pomeroy, Charles W.M. Roberts

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Emerging evidence demonstrates that subunits of the SWI/SNF chromatin remodeling complex are specifically mutated at high frequency in a variety of human cancer types. SNF5 (SMARCB1/INI1/BAF47), a core subunit of the SWI/SNF complex, is inactivated in the vast majority of rhabdoid tumors (RT), an aggressive type of pediatric cancer. SNF5-deficient cancers are diploid and genomically stable, suggesting that epigenetically based changes in transcription are key drivers of tumor formation caused by SNF5 loss. However, there is limited understanding of the target genes that drive cancer formation following SNF5 loss. Here we performed comparative expression analyses upon three independent SNF5-deficient cancer data sets from both human and mouse and identify downregulation of the BIN1 tumor suppressor gene as a conserved event in primary SNF5-deficient cancers. We show that SNF5 recruits the SWI/SNF complex to the BIN1 promoter, and that the marked reduction of BIN1 expression in RT correlates with decreased SWI/SNF occupancy. Functionally, we demonstrate that re-expression of BIN1 specifically compromises the proliferation of SNF5-deficient RT cell lines. Identification of BIN1 as a SNF5 target gene reveals a novel tumor suppressive regulatory mechanism whose disruption can drive cancer formation.

Original languageEnglish (US)
Pages (from-to)1956-1965
Number of pages10
JournalCell Cycle
Volume11
Issue number10
DOIs
StatePublished - May 15 2012

Keywords

  • BAF47
  • BIN1
  • INI1
  • Rhabdoid tumor
  • SMARCB1
  • SNF5

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    McKenna, E. S., Tamayo, P., Cho, Y. J., Tillman, E. J., Mora-Blanco, E. L., Sansam, C. G., Koellhoffer, E. C., Pomeroy, S. L., & Roberts, C. W. M. (2012). Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors. Cell Cycle, 11(10), 1956-1965. https://doi.org/10.4161/cc.20280