ARID1A-Mutated Cancers Are Sensitive to EZH2 Methyltransferase Inhibition

AT-rich interactive domain 1A (ARID1A), which encodes a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in many tumors including ovarian clear cell carcinoma (OCCC). Inactivation of this complex has been suggested to drive tumorigenesis through epigenetic mechanisms that alter gene expression; however, therapeutic strategies targeting ARID1A-mutated cancers have not been characterized. Using a screen of small-molecule epigenetic inhibitors, Bitler and colleagues identified GSK126, an inhibitor of the enhancer of zeste homolog 2 (EZH2) methyltransferase, which represses gene expression via trimethylation of histone H3 lysine 27 (H3K27Me3), as selective against ARID1A-depleted OCCC cells. Although GSK126 treatment effectively reduced overall H3K27Me3 levels in both wild-type and ARID1A-mutated cells, EZH2 inhibition selectively suppressed the growth of ARID1A-mutated OCCC cell lines via a reduction in proliferation and induction of apoptosis. Conversely, restoration of wild-type ARID1A expression resulted in decreased sensitivity to GSK126. Analysis of gene expression profiles identified the gene encoding PI3K-interacting protein 1 (PIK3IP1), which negatively regulates PI3K–AKT signaling, as a direct target of both EZH2 and ARID1A. PIK3IP1 expression was reduced in ARID1A-mutated OCCC cells, and GSK126 treatment or restoration of wild-type ARID1A resulted in its upregulation, suggesting that ARID1A and EZH2 antagonistically regulate PIK3IP1 expression. Consistent with this idea, both ARID1A and EZH2 bound the PIK3IP1 promoter in wild-type cells, with ARID1A playing a dominant role over EZH2 in driving PIK3IP1 expression. Knockdown of ARID1A resulted in reduced RNA polymerase II recruitment and EZH2-mediated suppression of PIK3IP1. PIK3IP1 depletion rescued GSK126-induced growth suppression and inhibited apoptosis in ARID1A-mutated cells, indicating that PIK3IP1 contributes to this synthetic lethality. Importantly, GSK126 treatment induced regression and decreased the dissemination of ARID1A-mutated, but not ARID1A–wild-type, xenograft tumors, which correlated with increased PIK3IP1 expression and decreased AKT activation. These results identify inhibition of EZH2 methyltransferase activity as a synthetic lethal therapeutic strategy to target ARID1A-mutated cancers.

Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 2015 Feb 16 [Epub ahead of print].