Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability

Elizabeth S. McKenna, Courtney G. Sansam, Yoon-Jae Cho, Heidi Greulich, Julia A. Evans, Christopher S. Thom, Lisa A. Moreau, Jaclyn A. Biegel, Scott L. Pomeroy, Charles W M Roberts

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deflcient primary cells do not show altered sensitivity to DNA damaging agents, defects in 7-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.

Original languageEnglish (US)
Pages (from-to)6223-6233
Number of pages11
JournalMolecular and Cellular Biology
Volume28
Issue number20
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

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Genomic Instability
Epigenomics
Neoplasms
Chromatin Assembly and Disassembly
Carcinogenesis
Diploidy
DNA Damage
Single Nucleotide Polymorphism
Maintenance
Genome
Phenotype
DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

McKenna, E. S., Sansam, C. G., Cho, Y-J., Greulich, H., Evans, J. A., Thom, C. S., ... Roberts, C. W. M. (2008). Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability. Molecular and Cellular Biology, 28(20), 6223-6233. https://doi.org/10.1128/MCB.00658-08

Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability. / McKenna, Elizabeth S.; Sansam, Courtney G.; Cho, Yoon-Jae; Greulich, Heidi; Evans, Julia A.; Thom, Christopher S.; Moreau, Lisa A.; Biegel, Jaclyn A.; Pomeroy, Scott L.; Roberts, Charles W M.

In: Molecular and Cellular Biology, Vol. 28, No. 20, 01.10.2008, p. 6223-6233.

Research output: Contribution to journalArticle

McKenna, ES, Sansam, CG, Cho, Y-J, Greulich, H, Evans, JA, Thom, CS, Moreau, LA, Biegel, JA, Pomeroy, SL & Roberts, CWM 2008, 'Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability', Molecular and Cellular Biology, vol. 28, no. 20, pp. 6223-6233. https://doi.org/10.1128/MCB.00658-08
McKenna, Elizabeth S. ; Sansam, Courtney G. ; Cho, Yoon-Jae ; Greulich, Heidi ; Evans, Julia A. ; Thom, Christopher S. ; Moreau, Lisa A. ; Biegel, Jaclyn A. ; Pomeroy, Scott L. ; Roberts, Charles W M. / Loss of the epigenetic tumor suppressor snf5 leads to cancer without genomic instability. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 20. pp. 6223-6233.
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