Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion

Isaac S. Harris, Jennifer E. Endress, Jonathan L. Coloff, Laura M. Selfors, Samuel K. McBrayer, Jennifer M. Rosenbluth, Nobuaki Takahashi, Sabin Dhakal, Vidyasagar Koduri, Matthew G. Oser, Nathan J. Schauer, Laura M. Doherty, Andrew L. Hong, Yun Pyo Kang, Scott T. Younger, John G. Doench, William C. Hahn, Sara J. Buhrlage, Gina M. DeNicola, William G. KaelinJoan S. Brugge

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1166-1181.e6
JournalCell Metabolism
Volume29
Issue number5
DOIs
StatePublished - May 7 2019
Externally publishedYes

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Harris, I. S., Endress, J. E., Coloff, J. L., Selfors, L. M., McBrayer, S. K., Rosenbluth, J. M., Takahashi, N., Dhakal, S., Koduri, V., Oser, M. G., Schauer, N. J., Doherty, L. M., Hong, A. L., Kang, Y. P., Younger, S. T., Doench, J. G., Hahn, W. C., Buhrlage, S. J., DeNicola, G. M., ... Brugge, J. S. (2019). Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. Cell Metabolism, 29(5), 1166-1181.e6. https://doi.org/10.1016/j.cmet.2019.01.020