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

Author

Listed:
  • Yibo Xue

    (McGill University
    McGill University
    McGill University
    McGill University)

  • Jordan L. Morris

    (University of Cambridge)

  • Kangning Yang

    (McGill University
    McGill University)

  • Zheng Fu

    (McGill University
    McGill University)

  • Xianbing Zhu

    (McGill University
    McGill University)

  • Fraser Johnson

    (British Columbia Cancer Agency
    University of British Columbia
    University of British Columbia)

  • Brian Meehan

    (McGill University)

  • Leora Witkowski

    (McGill University
    McGill University)

  • Amber Yasmeen

    (McGill University)

  • Tunde Golenar

    (McGill University
    McGill University)

  • Mackenzie Coatham

    (University of Alberta)

  • Geneviève Morin

    (McGill University
    McGill University)

  • Anie Monast

    (McGill University
    McGill University)

  • Virginie Pilon

    (McGill University
    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
    Queen’s University)

  • 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
    McGill University)

  • William Lockwood

    (British Columbia Cancer Agency
    University of British Columbia
    University of British Columbia)

  • William D. Foulkes

    (McGill University
    McGill University
    McGill University)

  • Julien Prudent

    (University of Cambridge)

  • Sidong Huang

    (McGill University
    McGill University)

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.

Suggested Citation

  • 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 Mon, 2021. "SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25260-9
    DOI: 10.1038/s41467-021-25260-9
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    Cited by:

    1. Xianbing Zhu & Zheng Fu & Shary Y. Chen & Dionzie Ong & Giulio Aceto & Rebecca Ho & Jutta Steinberger & Anie Monast & Virginie Pilon & Eunice Li & Monica Ta & Kyle Ching & Bianca N. Adams & Gian L. Ne, 2023. "Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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