TY - JOUR
T1 - The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53
AU - Hu, Chen
AU - Zhang, Mu
AU - Moses, Niko
AU - Hu, Cong li
AU - Polin, Lisa
AU - Chen, Wei
AU - Jang, Hyejeong
AU - Heyza, Joshua
AU - Malysa, Agnes
AU - Caruso, Joseph A.
AU - Xiang, Shengyan
AU - Patrick, Steve
AU - Stemmer, Paul
AU - Lou, Zhenkun
AU - Bai, Wenlong
AU - Wang, Chuangui
AU - Bepler, Gerold
AU - Zhang, Xiaohong Mary
N1 - Funding Information:
We would like to thank Dr. Johnathan M. Lancaster and Dr. Douglas Marchion for providing cell pellets of a panel of ovarian cancer cell lines, Mr. Noel Clark for immunohistochemical staining, Dr. Santo V. Nicosia for scoring the tumor tissue microarrays, Dr. Jia Fang for providing plasmids for DUBs. The work is supported in part by National Institutes of Health Grant R01CA164147, Karmanos Cancer Institute (KCI) Start-up funds, KCI internal funds, such as Epigenetic and Cancer funds and Molecular Therapeutics Program support funds, and Wayne State University Grants Boost Program to X.Z, NIH T32CA009531 grant to J.H., and Cancer Center Support Grant P30 CA022453 to G.B. The Wayne State University Proteomics Core Facility is supported through the NIH Center Grant P30 ES 020957, the NIH Cancer Center Support Grant P30 CA 022453 and the NIH Shared Instrumentation Grant S10 OD 010700. C.W. was partly supported by the National Natural Science Foundation of China (31671462, 31671433) and the National Key Research Program of China (2016YFC1304800).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Ubiquitin-specific peptidase 10 (USP10) stabilizes both tumor suppressors and oncogenes in a context-dependent manner. However, the nature of USP10’s role in non-small cell lung cancer (NSCLC) remains unclear. By analyzing The Cancer Genome Atlas (TCGA) database, we have shown that high levels of USP10 are associated with poor overall survival in NSCLC with mutant p53, but not with wild-type p53. Consistently, genetic depletion or pharmacological inhibition of USP10 dramatically reduces the growth of lung cancer xenografts lacking wild-type p53 and sensitizes them to cisplatin. Mechanistically, USP10 interacts with, deubiquitinates, and stabilizes oncogenic protein histone deacetylase 6 (HDAC6). Furthermore, reintroducing either USP10 or HDAC6 into a USP10-knockdown NSCLC H1299 cell line with null-p53 renders cisplatin resistance. This result suggests the existence of a “USP10-HDAC6-cisplatin resistance” axis. Clinically, we have found a positive correlation between USP10 and HDAC6 expression in a cohort of NSCLC patient samples. Moreover, we have shown that high levels of USP10 mRNA correlate with poor overall survival in a cohort of advanced NSCLC patients who received platinum-based chemotherapy. Overall, our studies suggest that USP10 could be a potential biomarker for predicting patient response to platinum, and that targeting USP10 could sensitize lung cancer patients lacking wild-type p53 to platinum-based therapy.
AB - Ubiquitin-specific peptidase 10 (USP10) stabilizes both tumor suppressors and oncogenes in a context-dependent manner. However, the nature of USP10’s role in non-small cell lung cancer (NSCLC) remains unclear. By analyzing The Cancer Genome Atlas (TCGA) database, we have shown that high levels of USP10 are associated with poor overall survival in NSCLC with mutant p53, but not with wild-type p53. Consistently, genetic depletion or pharmacological inhibition of USP10 dramatically reduces the growth of lung cancer xenografts lacking wild-type p53 and sensitizes them to cisplatin. Mechanistically, USP10 interacts with, deubiquitinates, and stabilizes oncogenic protein histone deacetylase 6 (HDAC6). Furthermore, reintroducing either USP10 or HDAC6 into a USP10-knockdown NSCLC H1299 cell line with null-p53 renders cisplatin resistance. This result suggests the existence of a “USP10-HDAC6-cisplatin resistance” axis. Clinically, we have found a positive correlation between USP10 and HDAC6 expression in a cohort of NSCLC patient samples. Moreover, we have shown that high levels of USP10 mRNA correlate with poor overall survival in a cohort of advanced NSCLC patients who received platinum-based chemotherapy. Overall, our studies suggest that USP10 could be a potential biomarker for predicting patient response to platinum, and that targeting USP10 could sensitize lung cancer patients lacking wild-type p53 to platinum-based therapy.
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U2 - 10.1038/s41419-020-2519-8
DO - 10.1038/s41419-020-2519-8
M3 - Article
C2 - 32382008
AN - SCOPUS:85084402957
SN - 2041-4889
VL - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - 328
ER -