SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca<sup>2+</sup> flux to mitochondria.
Fiset, Pierre Olivier
Gonzalez, Anne V
Gotlieb, Walter H
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Xue, Y., Morris, J. L., Yang, K., Fu, Z., Zhu, X., Johnson, F., Meehan, B., et al. (2021). SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca<sup>2+</sup> flux to mitochondria.. Nature communications, 12 (1) https://doi.org/10.1038/s41467-021-25260-9
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 (Ca<sup>2+</sup>) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca<sup>2+</sup> channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca<sup>2+</sup> 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 Ca<sup>2+</sup>-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.
Gouvernement du Canada | Canadian Institutes of Health Research (PJT-438303, MOP-130540, PJT-156233)
CIHR (MFE-171249, FDN-148390, PJT-156233, MOP-130540, PJT-438303)
Medical Research Council (MC_UU_00015/7)
External DOI: https://doi.org/10.1038/s41467-021-25260-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329518
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/