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-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in γ-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.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank Tom Curran for providing tumor samples and Yosef Shiloh, Satoshi Tateishi, and Alan D'Andrea for providing the positive-control cell lines for the DNA damage sensitivity assays. We also thank Neil J. Ganem for assistance with the preparation and imaging of mitotic cells, David Pellman and Alan D'Andrea for critical reading of the manuscript, and Rameen Beroukhim for helpful discussions.
The work was supported by PHS awards F32CA123776 (to C.G.S.), R01CA46274 (to J.A.B.), R01CA109467 (to S.L.P.), and R01CA113794 (to C.W.M.R). C.W.M.R. gratefully acknowledges support from the Garrett B. Smith Foundation, the Claudia Adams Barr Foundation, the Kate Lambert Rhabdoid Tumor Research Fund, and the Murphy Family Research Fund. C.G.S. gratefully acknowledges support from Hope Street Kids.
We declare no competing financial interests.