Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA.

Abstract

The BH3-only protein NOXA represents one of the critical mediators of DNA-damage-induced cell death. In particular, its involvement in cellular responses to cancer chemotherapy is increasingly evident. Here, we identify a strategy of cancer cells to escape genotoxic chemotherapy by increasing proteasomal degradation of NOXA. We show that the deubiquitylating enzyme UCH-L1 is a key regulator of NOXA turnover, which protects NOXA from proteasomal degradation by removing Lys(48)-linked polyubiquitin chains. In the majority of tumors from patients with melanoma or colorectal cancer suffering from high rates of chemoresistance, NOXA fails to accumulate because UCH-L1 expression is epigenetically silenced. Whereas UCH-L1/NOXA-positive tumor samples exhibit increased sensitivity to genotoxic chemotherapy, downregulation of UCH-L1 or inhibition of its deubiquitylase activity resulted in reduced NOXA stability and resistance to genotoxic chemotherapy in both human and C. elegans cells. Our data identify the UCH-L1/NOXA interaction as a therapeutic target for overcoming cancer chemoresistance.

• Authors: Kerstin Brinkmann, Paola Zigrino, Axel Witt, Michael Schell, Leena Ackermann, Pia Broxtermann, Stephan Schüll, Maria Andree, Oliver Coutelle, Benjamin Yazdanpanah, Jens Michael Seeger, Daniela Klubertz, Uta Drebber, Ulrich T Hacker, Martin Krönke, Cornelia Mauch, Thorsten Hoppe, Hamid Kashkar
• Journal: Cell reports (Cell Rep) Vol. 3 Issue 3 Pg. 881-91 (Mar 28 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 23499448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• UCHL1 protein, human
• Ubiquitin
• Ubiquitin Thiolesterase
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis
• Caenorhabditis elegans (drug effects, genetics, metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• DNA Damage
• Down-Regulation
• Drug Resistance, Neoplasm
• Gene Silencing
• Humans
• Melanoma (drug therapy)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Stability
• Proteolysis
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Small Interfering
• Ubiquitin (metabolism)
• Ubiquitin Thiolesterase (genetics, metabolism)
• Ubiquitination