Tumor Suppressive Function of ARID1A in Endometriosis-Associated Ovarian Cancer.

AT-rich interactive domain 1A (ARID1A) is found highly mutated in ovarian clear-cell carcinoma (OC-CC) and endometrioid ovarian cancers (EOC), cancers that are frequently associated with endometriosis. Based on the mutation pattern, a tumor suppressive role for ARID1A has been strongly suggested. However the underlying mechanisms are not well described. Consistent with a putative tumor suppressor, we find diminished expression of ARID1A in patient samples of endometrioid ovarian cancer with further decrease in expression in endometrioid ovarian cancers from women with endometriosis. Western blot confirms loss of ARID1A expression in several endometrioid and clear cell ovarian cancer cell lines. Over expression of wild type ARID1A in these cell lines results in coordinated inhibition of cellular proliferation and increased expression of cyclin dependent kinase inhibitors such as p21 and p27 (CDKN1A and CDKN1B). Importantly, these immortalized cell lines undergo significant cellular senescence as indicated by senescence-associated β-galactosidase expression. Cell cycle analysis reveals the induction of G1-phase arrest upon ARID1A over expression. Conversely, ARID1A knockdown in ARID1A-proficient cell lines results in a marked increase in cellular proliferation. Together, these data suggest that ARID1A may exert its tumor suppressive functions via regulation of the cell cycle and/or cellular senescence.