| Autor: |
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, Spicer, Jonathan, Gotlieb, Walter H., Guiot, Marie-Christine, Rak, Janusz, Park, Morag, Lockwood, William, Foulkes, William D., Prudent, Julien, Huang, Sidong |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
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