Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. As a core member of the Swi/Snf ATPase chromatin-remodeling complex, Snf5 (lni1/Baf47/SmarcB1) represents a newly recognized type of tumor suppressor. Accumulating evidence raises the possibility that perturbation of the Swi/Snf complex may have a widespread role in the genesis of numerous types of common cancers including those of lung, breast and prostate. Unlike complexes that covalently modify chromatin through methylation or acetylation of chromatin, the Swi/Snf complex does not leave a 'mark' and thus its role in oncogenesis is more difficult to detect. However, recent studies linking inactivation of Swi/Snf subunits to specific cancers as well as mouse modeling experiments, which demonstrate profound cancer formation following inactivation of Snf5, have established that the Swi/Snf complex serves a critical role in regulating growth and preventing oncogenic transformation. Since Snf5 is present in all variants of the Swi/Snf complex and it itself a bona fide tumor suppressor, our goal is to evaluate the function of Snf5 and determine how its loss leads to oncogenesis.
Specific Aims : (1) What is the role of Snf5 in T cell differentiation and why does its loss lead to T cell lymphoma? (2) What are the cellular consequences of Snf5 loss and how does this loss interact with mutations in known tumor suppressor genes? (3) What are the effects of Snf5 loss upon the activity of the Swi/Snf complex? Significance: The Swi/Snf complex is implicated in a variety of human cancers. Since Snf5 is present in all variants of the Swi/Snf complex and is itself a bona fide tumor suppressor, these studies will provide insight into this mechanism of tumor suppression. ? ? ?
| 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 |
| 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 |
| 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 |
| 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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