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Title: Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming
Author: 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
Keywords: Càncer
Issue Date: 7-Mar-2019
Publisher: American Society for Clinical Investigation
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: JCI Insight, 2019, vol. 5, p. 125888
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ISSN: 2379-3708
Appears in Collections: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))
Articles publicats en revistes (Ciències Fisiològiques)

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