SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca<sup>2+</sup> flux to mitochondria.
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Authors
Fu, Zheng
Zhu, Xianbing
Johnson, Fraser
Meehan, Brian
Yasmeen, Amber
Golenar, Tunde
Coatham, Mackenzie
Morin, Geneviève
Monast, Anie
Pilon, Virginie
Fiset, Pierre Olivier
Jung, Sungmi
Gonzalez, Anne V
Fu, Lili
Postovit, Lynne-Marie
Gotlieb, Walter H
Guiot, Marie-Christine
Publication Date
2021-09-13Journal Title
Nature communications
ISSN
2041-1723
Volume
12
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
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
Abstract
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.
Sponsorship
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)
Identifiers
PMC8438089, 34518526
External DOI: https://doi.org/10.1038/s41467-021-25260-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329518
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