@article{8b043bc4e4214a69b73a5ee3d3c213f0,
title = "Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion",
abstract = "Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy. Tumor initiation and progression lead to highly oxidative stress conditions. Harris et al. show that upon glutathione depletion, cancer cells rely on deubiquitinating enzymes to maintain protein homeostasis and cell viability. Combined inhibition of deubiquitinases and glutathione synthesis leads to proteotoxic and ER stress and cell death.",
keywords = "GCLC, HSF1, UPR, antioxidants, cancer, deubiquitinase, glutamate-cysteine ligase catalytic subunit, glutathione, heat shock factor 1, high-throughput screening, oxidative stress, proteotoxic stress, unfolded protein response",
author = "Harris, {Isaac S.} and Endress, {Jennifer E.} and Coloff, {Jonathan L.} and Selfors, {Laura M.} and McBrayer, {Samuel K.} and Rosenbluth, {Jennifer M.} and Nobuaki Takahashi and Sabin Dhakal and Vidyasagar Koduri and Oser, {Matthew G.} and Schauer, {Nathan J.} and Doherty, {Laura M.} and Hong, {Andrew L.} and Kang, {Yun Pyo} and Younger, {Scott T.} and Doench, {John G.} and Hahn, {William C.} and Buhrlage, {Sara J.} and DeNicola, {Gina M.} and Kaelin, {William G.} and Brugge, {Joan S.}",
note = "Funding Information: We would like to thank Alexander Muir, Ed Schmidt, and Angie Martinez Gakidis for critical reading of the manuscript. We would also like to thank Jennifer Smith, Caroline Shamu, and the entire staff at the ICCB-L for their assistance in the chemical screening. This work was supported by the Susan G. Komen for the Cure Foundation ( SAC170002 , J.S.B.), the Ludwig Center at Harvard (J.S.B.), Canadian Institutes of Health Research (I.S.H.), American Cancer Society MRSG-18-202-01-TBG (A.L.H.), Claudia Adams Barr Program (S.J.B.), NCI grant U01CA176058 (W.C.H.), NIH grant R37CA230042 (G.M.D.), NIH grant R35CA210068-02 (W.G.K.), and Howard Hughes Medical Institute (W.G.K.). Funding Information: We would like to thank Alexander Muir, Ed Schmidt, and Angie Martinez Gakidis for critical reading of the manuscript. We would also like to thank Jennifer Smith, Caroline Shamu, and the entire staff at the ICCB-L for their assistance in the chemical screening. This work was supported by the Susan G. Komen for the Cure Foundation (SAC170002, J.S.B.), the Ludwig Center at Harvard (J.S.B.), Canadian Institutes of Health Research (I.S.H.), American Cancer Society MRSG-18-202-01-TBG (A.L.H.), Claudia Adams Barr Program (S.J.B.), NCI grant U01CA176058 (W.C.H.), NIH grant R37CA230042 (G.M.D.), NIH grant R35CA210068-02 (W.G.K.), and Howard Hughes Medical Institute (W.G.K.). I.S.H. and J.S.B. initiated the study and conceived the project, designed experiments, interpreted results, and wrote the manuscript. I.S.H. performed the experiments with assistance from J.E.E. for high-throughput screening and validation of hits. J.L.C. and L.M.S. carried out bioinformatics analyses; J.M.R. human and mouse mammary organoid experiments; N.T. measuring of lipid peroxidation; S.D. xenograft experiments; Y.P.K. and G.M.D. TXN1 oxidation analysis; S.K.M. V.K. M.G.O. A.L.H. S.T.Y. J.G.D. W.C.H. and W.G.K. CRISPR-Cas9 experiments involving genetic screening; and N.J.S. L.M.D. and S.J.B. DUB engagement assay. J.S.B. receives funding from F. Hoffmann-La Roche Ltd and is a member of the Scientific Advisory Board (SAB) for eFFECTOR Therapeutics and Agios Pharmaceuticals. J.G.D. is a consultant to Tango Therapeutics. W.C.H. is a consultant to Thermo Fisher, AjuIB, Paraxel, and MPM Capital and is a founder and a member of the SAB for KSQ Therapeutics. W.C.H. receives funding from Deerfield. W.G.K. has financial interests related to Lilly Pharmaceuticals (Board of Directors), Agios Pharmaceuticals (SAB), Cedilla Therapeutics (Founder), FibroGen (SAB), Nextech Invest (SAB), Peloton Therapeutics (SAB), Tango Therapeutics (Founder), and Tracon Pharmaceuticals (SAB). W.G.K. is a coinventor on a patent entitled “Pharmaceuticals and Methods for Treating Hypoxia and Screening Methods Therefor” that has been licensed to FibroGen. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "7",
doi = "10.1016/j.cmet.2019.01.020",
language = "English (US)",
volume = "29",
pages = "1166--1181.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}