The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53

Chen Hu,Wenlong Bai,Wei Chen,Joseph A Caruso,Lisa Polin,Paul Stemmer,Mu Zhang,Steve Patrick,Chuangui Wang,Hyejeong Jang,Niko Moses,Joshua Heyza,Xiaohong Mary Zhang,Zhenkun Lou,Cong-Li Hu,Agnes Malysa,Shengyan Xiang,Gerold Bepler

doi:10.1038/s41419-020-2519-8

Abstract

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.

Highlights

Ubiquitin-specific peptidase 10 (USP10) belongs to the USP family[1]
USP10 interacts with histone deacetylase 6 (HDAC6) To investigate the role of USP10 in lung cancer, we employed a protein purification approach
To determine whether USP10 binds to HDAC6 directly or via other proteins, we generated and purified recombinant GST-USP10 and His-HDAC6 in E. coli

Summary

Introduction

Ubiquitin-specific peptidase 10 (USP10) belongs to the USP family[1]. The role of USP10 in cancer has remained elusive and complex, due to the diversity of its associated proteins and substrates[2,3,4,5,6,7,8,9,10,11]. As for USP10’s tumor type-specific role, we. The former serves as an oncogene in leukemia and a tumor suppressor in head and neck tumors[19,20]; the latter servers as an oncogene in breast cancer and a tumor suppressor in colon cancer[21,22]. USP10 plays an oncogenic role in breast cancer[23], glioblastoma[24], and prostate cancer[15], and serves as a tumor suppressor role in renal cell[5], gastric[25], and pancreatic cancers[26]. HDAC6 belongs to the class IIb HDAC family[27,28]. HDAC6 deacetylates a wide array of proteins, including α-tubulin[30], cortactin[31], Hsp9032, and MSH233

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Results

Conclusion