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

doi:10.1016/j.celrep.2013.02.014

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

46 Citations (Scopus)

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 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. Tumor cell resistance to chemotherapy continues to pose a challenge in anticancer therapy. NOXA is an important mediator of cell death in response to chemotherapy. Here, Kashkar and colleagues identify a strategy of cancer cells for escaping DNA-damaging chemotherapy by increasing turnover of NOXA. They further demonstrate that UCH-L1, which is silenced in numerous tumors, stabilizes NOXA by protecting it from degradation and thus identify the interaction of UCH-L1 and NOXA as a promising therapeutic target for overcoming chemoresistance in cancer.

Original language	English
Journal	Cell Reports
Volume	3
Issue number	3
Pages (from-to)	881-91
Number of pages	11
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2013.02.014
Publication status	Published - 28 Mar 2013

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2013.02.014Licence: CC BY-NC-ND

Cite this

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

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

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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 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. Tumor cell resistance to chemotherapy continues to pose a challenge in anticancer therapy. NOXA is an important mediator of cell death in response to chemotherapy. Here, Kashkar and colleagues identify a strategy of cancer cells for escaping DNA-damaging chemotherapy by increasing turnover of NOXA. They further demonstrate that UCH-L1, which is silenced in numerous tumors, stabilizes NOXA by protecting it from degradation and thus identify the interaction of UCH-L1 and NOXA as a promising therapeutic target for overcoming chemoresistance in cancer.",

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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",

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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

PY - 2013/3/28

Y1 - 2013/3/28

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 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. Tumor cell resistance to chemotherapy continues to pose a challenge in anticancer therapy. NOXA is an important mediator of cell death in response to chemotherapy. Here, Kashkar and colleagues identify a strategy of cancer cells for escaping DNA-damaging chemotherapy by increasing turnover of NOXA. They further demonstrate that UCH-L1, which is silenced in numerous tumors, stabilizes NOXA by protecting it from degradation and thus identify the interaction of UCH-L1 and NOXA as a promising therapeutic target for overcoming chemoresistance in cancer.

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 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. Tumor cell resistance to chemotherapy continues to pose a challenge in anticancer therapy. NOXA is an important mediator of cell death in response to chemotherapy. Here, Kashkar and colleagues identify a strategy of cancer cells for escaping DNA-damaging chemotherapy by increasing turnover of NOXA. They further demonstrate that UCH-L1, which is silenced in numerous tumors, stabilizes NOXA by protecting it from degradation and thus identify the interaction of UCH-L1 and NOXA as a promising therapeutic target for overcoming chemoresistance in cancer.

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

SN - 2211-1247

VL - 3

SP - 881

EP - 891

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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