Author, as appears in the article.: Llinàs-Arias P; Rosselló-Tortella M; López-Serra P; Pérez-Salvia M; Setién F; Marin S; Muñoz J; Junza A; Capellades J; Calleja-Cervantes M; Ferreira H; De Moura M; Srbic M; Martínez-Cardús A; De La Torre C; Villanueva A; Cascante M; Yanes O; Zorzano A; Moutinho C; Esteller M
Department: Enginyeria Electrònica, Elèctrica i Automàtica
URV's Author/s: Junza Martínez, Alexandra / Yanes Torrado, Óscar
Keywords: Uterine cervix cancer Unclassified drug Tanespimycin Small p97 vcp interacting protein Retaspimycin Proteomics Protein depletion Oncology Nuclear reprogramming Nonhuman Nms 873 Mouse Mitochondrial respiration Metabolomics Male In vivo study In vitro study Human tissue Human cell Human Hematologic malignancy Head and neck cancer Glucose Gene silencing Esophagus cancer Epigenetics Epigenetic repression Endoplasmic reticulum stress Eeyarestatin i Dna methylation Cpg island Controlled study Carcinogenesis Cancer inhibition Cancer cell line Cancer cell Cancer Bortezomib Binding protein Bay 876 B cell lymphoma Article Antineoplastic agent Antineoplastic activity Animal tissue Animal model Animal experiment Aerobic glycolysis
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.
Thematic Areas: Medicine, research & experimental Medicine (miscellaneous) Medicine (all) Medicina iii Medicina ii Medicina i General medicine Ciências biológicas ii
licence for use: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 23793708
Author's mail: oscar.yanes@urv.cat alexandra.junza@urv.cat
Author identifier: 0000-0003-3695-7157 0000-0001-7205-0419
Record's date: 2023-12-16
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://insight.jci.org/articles/view/125888
Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Jci Insight. 4 (8):
APA: Llinàs-Arias P; Rosselló-Tortella M; López-Serra P; Pérez-Salvia M; Setién F; Marin S; Muñoz J; Junza A; Capellades J; Calleja-Cervantes M; Ferreira H (2019). Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming. Jci Insight, 4(8), -. DOI: 10.1172/jci.insight.125888
Article's DOI: 10.1172/jci.insight.125888
Entity: Universitat Rovira i Virgili
Journal publication year: 2019
Publication Type: Journal Publications
Repositori URV