Acknowledgements: The authors thank A. Leary for sharing RNA-seq data and R. Hass for sharing the SCCOHT-1 cells. The authors thank members of the Pelletier Laboratory for assistance with flow cytometry studies. This work was supported by Canadian Institutes of Health Research (CIHR) grants MOP-130540, PJT-156233, and PJT-438303 to S.H. and grant FDN-148390 to W.D.F. and a core grant from Medical Research Council (MRC) MC_UU_00015/7 to J.P. Author Y.X. was supported by CIHR Fellowship (MFE-171249), J.L.M. was supported by a MRC-funded graduate student fellowship, and S.H. was supported by a CRC Chair in Functional Genomics.Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers
