Cancer genome sequencing studies have now revealed that genes that encode nine different subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in a wide variety of human cancers. These include cancers of brain, ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver, skin and blood. Collectively, over twenty percent of all human cancers contain a SWI/SNF mutation making SWI/SNF complexes the most frequently mutated chromatin/epigenetic regulator in cancer. During the current funding cycle we have made notable progress in elucidating the functions of SWI/SNF complexes. However, major questions have subsequently emerged. SWI/SNF complexes consist of both core subunits and variant subunits, with the latter present in only sub-classes of complexes. It has now become clear that the frequently mutated subunits are all variant subunits including ARID1A, SMARCA4 and PBRM1 and that mutation of each is associated with a distinct cancer spectrum. However, the mechanistic and functional contributions of these variant subunits and sub-classes to SWI/SNF function is poorly understood. We hypothesize that oncogenesis occurs not due to broad loss of SWI/SNF complex function but rather due to aberrant function of residual SWI/SNF complexes. We further hypothesize that loss of the variant tumor-suppressor subunits alters the composition, targeting and chromatin remodeling activity of SWI/SNF thus impairing differentiation and promoting oncogenesis. Using our genetically engineered primary cells, cell lines and mice, we will address three aims:
Aim 1 : How do the mutually exclusive ATPase subunits of SWI/SNF complexes, SMARCA4/BRG1 and SMARCA2/BRM, differ in function and what is the mechanistic basis for the synthetic lethality of SMARCA2 in SMARCA4 mutant cancers? Aim 2: How does the PBRM1-containig PBAF sub-class of SWI/SNF complexes differ from the ARID1A/B-containing BAF sub-class with respect to composition, targeting, chromatin remodeling activity, enhancer regulation and control of lineage specification? Aim 3: How does our newly discovered BRD9- containing sub-class differ in composition and function from other SWI/SNF sub-classes, and can BRD9 be exploited as a therapeutic target?
Cancer genome sequencing studies have revealed that at least nine genes that encode subunits of SWI/SNF chromatin remodeling complexes are mutated at high frequency in a variety of human cancers. It is the variant subunits, those that are present only in sub-families of SWI/SNF complexes, that are frequently mutated. However, the mechanistic and functional contributions of these subunits and their sub-classes to SWI/SNF function is poorly understood. Study of SWI/SNF complexes is the central focus of my research laboratory and here we propose experimental studies to determine the function of the most frequently mutated variant subunits, to determine how mutation of these subunits cause cancer growth, with a specific goal of identifying new and effective therapeutic targets for these cancers.
| 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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