Mechanism of Tumorigenesis by Cancer-Associated Mutations of INI1/SMARCB1, a Component of the SWI/SNF Chromatin Remodeling Complex
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One of the core components of the chromatin remodeling complex SWI/SNF that are frequently mutated in human cancers is INI1/SMARCB1. Some of INI1/SMARCB1 mutations, found in rhabdoid tumors-RT (S284L, P48S) and schwannomatosis-SW (PI4H, R53L), are cancer-associated (CA) missense mutations expressing stable full-length INI1/SMARCB1. Since the reintroduction of INI1/SMARCB1 into RT cells have shown to induce cell cycle arrest, senescence, and transcriptional dysregulation of a few downstream genes, we hypothesized that these CA-INI1/SMARCB1 mutants could be defective for one or more of those functions, resulting in tumorigenesis in RT and SW. Therefore, we analyzed the physiological and transcriptional changes of RT cells upon the reintroduction of INI1/SMARCB1 or CA-INI1/SMARCB1 mutants and found that some but not all CA-INI1/SMARCB1 mutants were defective for inducing cell cycle arrest. However, they were all defective for inducing senescence and three out of four were defective for activating GBP1 (guanylate binding protein 1). We further confirmed that the ectopic expression of GBPI in RT cells can induce senescence in the absence of INI1/SMARCB1, and INI1/SMARCB1 requires GBP1 for a fully effective induction of senescence in RT cells. These evidences, for the first time, showed that the evasion of senescence was a mechanism by which CA-INI1/SMARCB1 mutants generated tumors.;To further understand the mechanism behind the inability of CA-INI1/SMARCB1 mutants to regulate transcription and induce senescence, their interaction with cMYC, a major known transcription factor deregulated in many cancers, and an important binding partner of INI1/SMARCB1, was tested. All CA-INI1/SMARCB1 mutants were found to be defective for interacting with cMYC, as well as for the repression of a few cMYC downstream transcription factors, including FOXM1 (forkhead box protein M1), a major mediator of cell cycle progression. Treatment of RT cells with CDK4/CDK6 inhibitor PD0332991 drug, which would target FOXM1 phosphorylation, led to the inhibition of cell proliferation, G2 cell cycle arrest, and induction of senescence. These studies, for the first time, indicated that CA-INI1/SMARCB1 mutants were defective for regulating cMYC and that interfering with activation of a cMYC target, FOXM1, was a novel strategy to inhibit tumor cell growth and induce senescence in RT cells.
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