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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Kerstin Brinkmann
  • Paola Zigrino
  • Axel Witt
  • Michael Schell
  • Ackermann, Leena
  • 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

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.

Original languageEnglish
JournalCell Reports
Volume3
Issue number3
Pages (from-to)881-91
Number of pages11
ISSN2211-1247
DOIs
Publication statusPublished - 28 Mar 2013

    Research areas

  • Animals, Antineoplastic Agents/pharmacology, Apoptosis, Caenorhabditis elegans/drug effects, 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, RNA, Small Interfering, Ubiquitin/metabolism, Ubiquitin Thiolesterase/genetics, Ubiquitination

ID: 203248672