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

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.

• Authors: Chen Hu, Mu Zhang, Niko Moses, Cong-Li Hu, Lisa Polin, Wei Chen, Hyejeong Jang, Joshua Heyza, Agnes Malysa, Joseph A Caruso, Shengyan Xiang, Steve Patrick, Paul Stemmer, Zhenkun Lou, Wenlong Bai, Chuangui Wang, Gerold Bepler, Xiaohong Mary Zhang
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 5 Pg. 328 (05 07 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32382008 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• USP10 protein, human
• Platinum
• Ubiquitin Thiolesterase
• Histone Deacetylase 6
• Cisplatin

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Histone Deacetylase 6 (metabolism)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice, SCID
• Mutation (genetics)
• Ovarian Neoplasms (pathology)
• Platinum (pharmacology)
• Protein Binding (drug effects)
• Protein Stability (drug effects)
• Signal Transduction (drug effects)
• Substrate Specificity (drug effects)
• Tumor Suppressor Protein p53 (deficiency, metabolism)
• Ubiquitin Thiolesterase (metabolism)
• Ubiquitination (drug effects)
• Xenograft Model Antitumor Assays