SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria

Yibo Xue, Jordan L. Morris, Kangning Yang, Zheng Fu, Xianbing Zhu, Fraser Johnson, Brian Meehan, Leora Witkowski, Amber Yasmeen, Tunde Golenar, Mackenzie Coatham, Geneviève Morin, Anie Monast, Virginie Pilon, Pierre Olivier Fiset, Sungmi Jung, Anne V. Gonzalez, Sophie Camilleri-Broet, Lili Fu, Lynne-Marie Postovit, Jonathan Spicer, Walter H. Gotlieb, Marie-Christine Guiot, Janusz Rak, Morag Park, William Lockwood, William D. Foulkes, Julien Prudent () and Sidong Huang ()
Additional contact information
Yibo Xue: McGill University
Jordan L. Morris: University of Cambridge
Kangning Yang: McGill University
Zheng Fu: McGill University
Xianbing Zhu: McGill University
Fraser Johnson: British Columbia Cancer Agency
Brian Meehan: McGill University
Leora Witkowski: McGill University
Amber Yasmeen: McGill University
Tunde Golenar: McGill University
Mackenzie Coatham: University of Alberta
Geneviève Morin: McGill University
Anie Monast: McGill University
Virginie Pilon: McGill University
Pierre Olivier Fiset: McGill University Health Centre
Sungmi Jung: McGill University Health Centre
Anne V. Gonzalez: Montreal Chest Institute
Sophie Camilleri-Broet: McGill University Health Centre
Lili Fu: McGill University Health Centre
Lynne-Marie Postovit: University of Alberta
Jonathan Spicer: McGill University Health Center
Walter H. Gotlieb: McGill University
Marie-Christine Guiot: McGill University Health Centre
Janusz Rak: McGill University
Morag Park: McGill University
William Lockwood: British Columbia Cancer Agency
William D. Foulkes: McGill University
Julien Prudent: University of Cambridge
Sidong Huang: McGill University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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 (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.

Date: 2021
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DOI: 10.1038/s41467-021-25260-9

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