ARID1A loss in cancer: Towards a mechanistic understanding

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Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in 20% of all human cancers. ARID1A is the SWI/SNF subunit gene that is most frequently mutated, at variable frequencies across molecular and histological subtypes of cancer. Mouse modeling has revealed that the role of ARID1A in tumor suppression is highly dependent upon context. Recent mechanistic studies have identified a crucial role for ARID1A in targeting SWI/SNF complexes to tissue-specific enhancers and in maintaining their chromatin accessibility. In the absence of ARID1A, defects in control of enhancer activity impair developmental programs and cause extensive dysregulation of gene expression, thus driving tumor formation. Roles for ARID1A have also been described in other processes linked to tumor suppression including control of the cell cycle/DNA damage checkpoint, regulation of P53 targets, and telomerase activation. Here, we synthesize a mechanistic understanding of the role of ARID1A in tumor suppression and discuss the implications of these new discoveries for therapy.

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