Cancer-based discovery of novel mechanisms of chromatin control
NIH
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Project Summary/Abstract: The systematic sequencing of cancer genomes has revealed a high prevalence of mutations in genes encoding chromatin regulatory proteins. Of these aberrations, mutations in genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are the most frequent, collectively occurring in over 20% of all cancers. Whereas most genes that are mutated at such high frequencies in cancer have been studied for many decades, recognition of a prominent role for SWI/SNF mutations is much more recent. The first link between SWI/SNF and cancer came when the gene encoding the SMARCB1 subunit was found to be biallelically inactivated in nearly all cases of the highly aggressive and lethal cancer of early childhood termed malignant rhabdoid tumor (RT). Notably, these RT cancers are genomically stable and diploid, rendering them a highly useful model in which to study the effects of SWI/SNF disruption. Our long-term goals are to elucidate the function of SWI/SNF complexes, to determine how their loss leads to oncogenesis, and to translate this understanding into novel highly effective therapies. Our group established SMARCB1 to be a bona fide and potent tumor suppressor and later made high-impact discoveries that help define mechanisms by which SWI/SNF mutations lead to dysregulated cell proliferation. Our findings to date suggest a model whereby SWI/SNF-facilitated control of transcription underlies cellular fate specification, with disruption of this control being the basis for cancer formation. We hypothesized that loss of SMARCB1, while driving cancer growth, also creates unique vulnerabilities. To identify such vulnerabilities, we undertook a rigorous screen involving 21 RT cell lines compared to 800 other cancer cell lines. From this screen, we identified and subsequently validated two novel genes as being required specifically and potently for RT cell survival. Using multiple approaches and tools, we have validated both genes as specifically essential in RT cells. Our subsequent preliminary data reveal that both genes have unanticipated novel roles in chromatin regulation: both regulate active chromatin and specifically facilitate acetylation of lysine residues on histone H3 that facilitate transcription of target genes. We now hypothesize that these genes cooperate with SWI/SNF complexes, and that elucidation of their function will provide novel insights into chromatin-mediated regulation of transcription, mechanisms by which mutation of SWI/SNF subunits drive cancer, and vulnerabilities created by SWI/SNF mutations. Additionally, both genes bring the opportunity for therapeutic targeting. In the proposed work, we will define the mechanistic relationship between these genes and SWI/SNF and determine the mechanism underlying the specific vulnerabilities in RT. Taken together, these efforts have potential for substantial impact by broadening understanding of the roles of chromatin regulators in normal cells and in transformation and by identifying highly specific new therapeutic targets for these lethal childhood cancers. Project Narrative: Mutation of genes involved in chromatin regulation frequently underlie cancer. We have identified and validated two genes that when deleted, cause cell death specifically in childhood cancers mutant for the SWI/SNF chromatin remodeler subunit SMARCB1. The proposed studies are designed to determine the normal function of these two genes and to define the mechanisms by which they kill these childhood cancers, with the ultimate goal of yielding new therapeutic approaches.
Non-SBIR/STTR