Epigenetic loss of the endoplasmic reticulum–associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming
Pere Llinàs-Arias, … , Catia Moutinho, Manel Esteller
Pere Llinàs-Arias, … , Catia Moutinho, Manel Esteller
Published March 7, 2019
Citation Information: JCI Insight. 2019;4(8):e125888. https://doi.org/10.1172/jci.insight.125888.
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Research Article Oncology

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

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.

Authors

Pere Llinàs-Arias, Margalida Rosselló-Tortella, Paula López-Serra, Montserrat Pérez-Salvia, Fernando Setién, Silvia Marin, Juan P. Muñoz, Alexandra Junza, Jordi Capellades, María E. Calleja-Cervantes, Humberto J. Ferreira, Manuel Castro de Moura, Marina Srbic, Anna Martínez-Cardús, Carolina de la Torre, Alberto Villanueva, Marta Cascante, Oscar Yanes, Antonio Zorzano, Catia Moutinho, Manel Esteller

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Figure 2

SVIP features tumor suppressor activities in vitro and in vivo.

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SVIP features tumor suppressor activities in vitro and in vivo. (A) Effi...
(A) Efficient restoration of SVIP expression upon transfection in BB30-HNC cells according to qPCR (left) and Western blot (right). qPCR values are represented as mean of biological triplicates and analyzed using a 2-tailed Student’s t test. (B) SRB assay shows that SVIP transfection reduces viability of BB30-HNC cells. This graph is representative of 3 independent experiments. Each data point represents mean ± SD. Statistical differences were determined using a 2-tailed Student’s t test at the 144-hour time point. (C) Efficient shRNA-mediated depletion of SVIP according to qPCR (left) and Western blot (right) in the unmethylated Ca9-22 head and neck cancer cell line. qPCR values are represented as mean of biological triplicates and analyzed using a 2-tailed Student’s t test. Two shRNA clones are shown. (D) SRB assay shows that SVIP shRNA-mediated depletion increases viability of Ca9-22 cells. This graph is representative of 3 independent experiments. Each data point represents mean ± SD. Statistical differences were determined using a 2-tailed Student’s t test at the 144-hour time point. (E) Empty vector–transfected (EV-transfected) and SVIP-transfected BB30-HNC cells were injected into the left and right flank, respectively, of 10 mice. Tumor volume over time (left) and tumor weight upon sacrifice (right) are shown. Tumor growth and weight were analyzed using a 2-tailed Student’s t test. Data shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. ns, not significant.