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2019-03-07

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/153219

Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming

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https://doi.org/10.1172/jci.insight.125888

Resum

The endoplasmic reticulum (ER) of cancer cells needs to adapt to the enhanced proteotoxic stress associated with the accumulation of unfolded, misfolded and transformation-associated proteins. One way by which tumors thrive in the context of ER stress is by promoting ER-Associated Degradation (ERAD), although the mechanisms are poorly understood. Here, we show that the Small p97/VCP Interacting Protein (SVIP), an endogenous inhibitor of ERAD, undergoes DNA hypermethylation-associated silencing in tumorigenesis to achieve this goal. SVIP exhibits tumor suppressor features and its recovery is associated with increased ER stress and growth inhibition. Proteomic and metabolomic analyses show that cancer cells with epigenetic loss of SVIP are depleted in mitochondrial enzymes and oxidative respiration activity. This phenotype is reverted upon SVIP restoration. The dependence of SVIP hypermethylated cancer cells on aerobic glycolysis and glucose was also associated with sensitivity to an inhibitor of the glucose transporter GLUT1. This could be relevant to the management of tumors carrying SVIP epigenetic loss, because these occur in high-risk patients who manifest poor clinical outcomes. Overall, our study provides insights into how epigenetics helps deal with ER stress and how SVIP epigenetic loss in cancer may be amenable to therapies that target glucose transporters.

Matèries

Càncer, Epigenètica, Oncologia

Matèries (anglès)

Cancer, Epigenetics, Oncology

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Col·leccions

Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

Citació

LLINÀS-ARIAS, Pere, ROSSELLÓ-TORTELLA, Margalida, LÓPEZ SERRA, Paula, PÉREZ SALVIA, Montserrat, SETIÉN, Fernando, MARIN, Silvia, MUÑOZ, Juan pablo, JUNZA MARTÍNEZ, Alexandra, CAPELLADES, Jordi, CALLEJA CERVANTES, Maria e., FERREIRA, Humberto j., CASTRO DE MOURA, Manuel, SRBIC, Marina, MARTÍNEZ CARDÚS, Anna, TORRE GÓMEZ, Carolina de la, VILLANUEVA GARATACHEA, Alberto, CASCANTE I SERRATOSA, Marta, YANES, Oscar, ZORZANO OLARTE, Antonio, MOUTINHO, Cátia, ESTELLER, Manel. Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming. _JCI Insight_. 2019. Vol. 5, núm. 125888. [consulta: 23 de gener de 2026]. ISSN: 2379-3708. [Disponible a: https://hdl.handle.net/2445/153219]

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