Repository logo

SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca 2+ flux to mitochondria

Published version

Change log


Fu, Zheng 
Zhu, Xianbing 


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.


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.


Article, /631/67/68/2486, /631/67/1059/2326, /631/67/1244, /631/80/82/23, /13/106, /13/89, /13/95, /13/44, /13/51, /13/31, /13/2, /14/19, /38/15, /38/39, /49/47, /82/80, article

Journal Title

Conference Name

Journal ISSN


Volume Title


Nature Publishing Group UK
Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) (MOP-130540, PJT-156233, PJT-438303)