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 - 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 -