Most, if not all, cancers have epigenetic changes, which are proposed to contribute to oncogenesis. However, it is difficult to evaluate the contribution of epigenetic changes in the setting of genome instability. SNF5 (INI1/SMARCB1/BAF47) is specifically mutated in aggressive human cancers and in a familial cancer predisposition syndrome. In the previous funding period we found that SNF5 loss does not affect DNA repair or chromosome stability but rapidly leads to aggressive cancers that lack genome instability and possess widespread epigenetic alterations. While it has been hypothesized that SNF5 loss leads to inactivation of the SWI/SNF complex, we have additional evidence that tumorigenesis is rather caused by aberrant activation of the residual complex. Indeed, SNF5-deficient cancers are abolished by concomitant loss of BRG1, the core ATPase of the SWI/SNF complex. This proposal will exploit unique reagents developed in the laboratory to test our hypothesis that cancer caused by SNF5 loss is driven by dysfunctional nucleosome position at specific promoters caused by neomorphic effects of a partially functional SWI/SNF complex and we will also identify the epigenetically regulated pathways that cooperate with SNF5 loss.
Aim 1 : What are the effects of Snf5 inactivation upon nucleosome positioning? Aim 2: What are the effects of Snf5 loss upon the targeting and composition of the Swi/Snf complex? Aim 3: What genes cooperate with Snf5 loss in oncogenic transformation? Significance: The Swi/Snf complex is mutated in a variety of human cancers. No studies have evaluated the role of SNF5 in nucleosome remodeling or targeting, fundamental activities of the SWI/SNF complex. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of an epigenetic regulator causes the rapid onset of aggressive, lethal cancers in the absence of genome instability and identify novel epigenetically based targets for therapeutic intervention.
SNF5 and other subunits of the SWI/SNF chromatin remodeling complex are specifically mutated in a variety of aggressive human cancers and in a familial cancer syndrome. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of this complex causes the rapid onset of aggressive, lethal cancers and identify novel targets for therapeutic intervention.
| Kuwahara, Yasumichi; Kennedy, Leslie M; Karnezis, Anthony N et al. (2018) High Frequency of Ovarian Cyst Development in Vhl2B/+;Snf5+/- Mice. Am J Pathol 188:1510-1516 |
| Wang, Xiaofeng; Lee, Ryan S; Alver, Burak H et al. (2017) SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 49:289-295 |
| Mathur, Radhika; Alver, Burak H; San Roman, Adrianna K et al. (2017) ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49:296-302 |
| Alver, Burak H; Kim, Kimberly H; Lu, Ping et al. (2017) The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat Commun 8:14648 |
| Kim, Kimberly H; Roberts, Charles W M (2016) Targeting EZH2 in cancer. Nat Med 22:128-34 |
| Frühwald, Michael C; Biegel, Jaclyn A; Bourdeaut, Franck et al. (2016) Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies. Neuro Oncol 18:764-78 |
| Yin, Jie; Leavenworth, Jianmei W; Li, Yang et al. (2015) Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci U S A 112:15988-93 |
| Kim, Kimberly H; Kim, Woojin; Howard, Thomas P et al. (2015) SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med 21:1491-6 |
| Wu, Jennifer N; Pinello, Luca; Yissachar, Elinor et al. (2015) Functionally distinct patterns of nucleosome remodeling at enhancers in glucocorticoid-treated acute lymphoblastic leukemia. Epigenetics Chromatin 8:53 |
| Helming, Katherine C; Wang, Xiaofeng; Roberts, Charles W M (2014) Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26:309-317 |
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