title: 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.affiliation: Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brinkmann
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
authors.forename: Axel
authors.initials: A
authors.lastname: Witt
authors.forename: Michael
authors.initials: M
authors.lastname: Schell
authors.forename: Leena
authors.initials: L
authors.lastname: Ackermann
authors.forename: Pia
authors.initials: P
authors.lastname: Broxtermann
authors.forename: Stephan
authors.initials: S
authors.lastname: Schüll
authors.forename: Maria
authors.initials: M
authors.lastname: Andree
authors.forename: Oliver
authors.initials: O
authors.lastname: Coutelle
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yazdanpanah
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Seeger
authors.forename: Daniela
authors.initials: D
authors.lastname: Klubertz
authors.forename: Uta
authors.initials: U
authors.lastname: Drebber
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hacker
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hoppe
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004249:DNA Damage; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C482860:UCHL1 protein, human; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex