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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. / Brinkmann, Kerstin; Zigrino, Paola; Witt, Axel; Schell, Michael; Ackermann, Leena; Broxtermann, Pia; Schüll, Stephan; Andree, Maria; Coutelle, Oliver; Yazdanpanah, Benjamin; Seeger, Jens Michael; Klubertz, Daniela; Drebber, Uta; Hacker, Ulrich T; Krönke, Martin; Mauch, Cornelia; Hoppe, Thorsten; Kashkar, Hamid.

In: Cell Reports, Vol. 3, No. 3, 2013, p. 881-91.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Brinkmann, K, Zigrino, P, Witt, A, Schell, M, Ackermann, L, Broxtermann, P, Schüll, S, Andree, M, Coutelle, O, Yazdanpanah, B, Seeger, JM, Klubertz, D, Drebber, U, Hacker, UT, Krönke, M, Mauch, C, Hoppe, T & Kashkar, H 2013, 'Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA', Cell Reports, vol. 3, no. 3, pp. 881-91. https://doi.org/10.1016/j.celrep.2013.02.014

APA

Brinkmann, K., Zigrino, P., Witt, A., Schell, M., Ackermann, L., Broxtermann, P., Schüll, S., Andree, M., Coutelle, O., Yazdanpanah, B., Seeger, J. M., Klubertz, D., Drebber, U., Hacker, U. T., Krönke, M., Mauch, C., Hoppe, T., & Kashkar, H. (2013). Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. Cell Reports, 3(3), 881-91. https://doi.org/10.1016/j.celrep.2013.02.014

Vancouver

Brinkmann K, Zigrino P, Witt A, Schell M, Ackermann L, Broxtermann P et al. Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. Cell Reports. 2013;3(3):881-91. https://doi.org/10.1016/j.celrep.2013.02.014

Author

Brinkmann, Kerstin ; Zigrino, Paola ; Witt, Axel ; Schell, Michael ; Ackermann, Leena ; Broxtermann, Pia ; Schüll, Stephan ; Andree, Maria ; Coutelle, Oliver ; Yazdanpanah, Benjamin ; Seeger, Jens Michael ; Klubertz, Daniela ; Drebber, Uta ; Hacker, Ulrich T ; Krönke, Martin ; Mauch, Cornelia ; Hoppe, Thorsten ; Kashkar, Hamid. / Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. In: Cell Reports. 2013 ; Vol. 3, No. 3. pp. 881-91.

Bibtex

@article{ed3326fc496c4d6aa0ccb85a3cf1c8c3,
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.",
keywords = "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",
author = "Kerstin Brinkmann and Paola Zigrino and Axel Witt and Michael Schell and Leena Ackermann and Pia Broxtermann and Stephan Sch{\"u}ll and Maria Andree and Oliver Coutelle and Benjamin Yazdanpanah and Seeger, {Jens Michael} and Daniela Klubertz and Uta Drebber and Hacker, {Ulrich T} and Martin Kr{\"o}nke and Cornelia Mauch and Thorsten Hoppe and Hamid Kashkar",
note = "Copyright {\textcopyright} 2013 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2013",
doi = "10.1016/j.celrep.2013.02.014",
language = "English",
volume = "3",
pages = "881--91",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA

AU - Brinkmann, Kerstin

AU - Zigrino, Paola

AU - Witt, Axel

AU - Schell, Michael

AU - Ackermann, Leena

AU - Broxtermann, Pia

AU - Schüll, Stephan

AU - Andree, Maria

AU - Coutelle, Oliver

AU - Yazdanpanah, Benjamin

AU - Seeger, Jens Michael

AU - Klubertz, Daniela

AU - Drebber, Uta

AU - Hacker, Ulrich T

AU - Krönke, Martin

AU - Mauch, Cornelia

AU - Hoppe, Thorsten

AU - Kashkar, Hamid

N1 - Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis

KW - Caenorhabditis elegans/drug effects

KW - Cell Line, Tumor

KW - Colorectal Neoplasms/drug therapy

KW - DNA Damage

KW - Down-Regulation

KW - Drug Resistance, Neoplasm

KW - Gene Silencing

KW - Humans

KW - Melanoma/drug therapy

KW - Proteasome Endopeptidase Complex/metabolism

KW - Protein Stability

KW - Proteolysis

KW - Proto-Oncogene Proteins c-bcl-2/genetics

KW - RNA, Small Interfering

KW - Ubiquitin/metabolism

KW - Ubiquitin Thiolesterase/genetics

KW - Ubiquitination

U2 - 10.1016/j.celrep.2013.02.014

DO - 10.1016/j.celrep.2013.02.014

M3 - Journal article

C2 - 23499448

VL - 3

SP - 881

EP - 891

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -

ID: 203248672