We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca<sup>2+</sup> flux to mitochondria.
- Authors
Xue, Yibo; Morris, Jordan L.; Yang, Kangning; Fu, Zheng; Zhu, Xianbing; Johnson, Fraser; Meehan, Brian; Witkowski, Leora; Yasmeen, Amber; Golenar, Tunde; Coatham, Mackenzie; Morin, Geneviève; Monast, Anie; Pilon, Virginie; Fiset, Pierre Olivier; Jung, Sungmi; Gonzalez, Anne V.; Camilleri-Broet, Sophie; Fu, Lili; Postovit, Lynne-Marie
- 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. SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca2+ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.
- Subjects
CELL death; MITOCHONDRIA; INTRACELLULAR calcium; ENDOPLASMIC reticulum; APOPTOSIS; HISTONE deacetylase inhibitors; CALCIUM ions; CANCER cells
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-25260-9