Ubiquitin C-Terminal Hydrolase-L1 Potentiates Cancer Chemosensitivity by Stabilizing NOXA
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
Affiliations
Kerstin Brinkmann
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Paola Zigrino
Department of Dermatology, University Hospital of Cologne, 50937 Cologne, Germany
Axel Witt
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Michael Schell
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany
Leena Ackermann
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany
Pia Broxtermann
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Stephan Schüll
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Maria Andree
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Oliver Coutelle
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Benjamin Yazdanpanah
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Jens Michael Seeger
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Daniela Klubertz
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Uta Drebber
Institute of Pathology, University Hospital of Cologne, 50937 Cologne, Germany
Ulrich T. Hacker
Department of Internal Medicine I, University Hospital of Cologne, 50924 Cologne, Germany
Martin Krönke
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
Cornelia Mauch
Department of Dermatology, University Hospital of Cologne, 50937 Cologne, Germany
Thorsten Hoppe
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany
Hamid Kashkar
Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, 50935 Cologne, Germany
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 Lys48-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.
