ARID1B as a Potential Therapeutic Target for ARID1A-Mutant Ovarian Clear Cell Carcinoma

Abstract

AT-rich interactive domain 1A (ARID1A) and AT-rich interactive domain 1B (ARID1B) are subunits of the SWI/SNF chromatin complex. ARID1A is a tumor suppressor gene that is frequently mutated (46%) in ovarian clear cell carcinomas (OCCC). Loss of ARID1B in an ARID1A-deficient background eliminates the intact SWI/SNF complex, indicating that ARID1B is essential for the formation or stabilization of an intact SWI/SNF complex and, thus, the survival of ARID1A-mutant cancer cell lines. In this study, we investigated the clinicopathologic and prognostic relevance of ARID1B in OCCC by immunohistochemical analysis of 53 OCCC patient samples and loss-of-function experiments in OCCC cell lines. We also examined whether ARID1B could be a therapeutic target or prognostic biomarker in OCCC. siRNA-mediated knockdown of ARID1B in an ARID1A-mutant cell line significantly decreased cell growth, whereas concurrent depletion of both ARID1A and ARID1B was required to decrease wild type cell growth. In the immunohistochemical analyses, low ARID1B level was frequent in samples lacking ARID1A and was associated with shorter progression-free survival. This is the first report demonstrating that a low ARID1B level could be a marker of poor prognosis in OCCC. Moreover, the correlation between the loss of ARID1A immunoreactivity and reduced ARID1B levels indicates that ARID1B could be an attractive target for anti-cancer therapy.