Department of Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R. St., Detroit, MI, 48201, USA.
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.
Cell Death Dis. 2020 May 7;11(5):328. doi: 10.1038/s41419-020-2519-8.
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.
泛素特异性肽酶 10（USP10）以依赖于上下文的方式稳定肿瘤抑制因子和癌基因。然而，USP10 在非小细胞肺癌（NSCLC）中的作用性质仍不清楚。通过分析癌症基因组图谱（TCGA）数据库，我们表明在具有突变型 p53 的 NSCLC 中，USP10 水平高与总生存期差相关，但与野生型 p53 无关。一致地，USP10 的遗传缺失或药理学抑制可显著降低缺乏野生型 p53 的肺癌异种移植物的生长，并使其对顺铂敏感。在机制上，USP10 与致癌蛋白组蛋白去乙酰化酶 6（HDAC6）相互作用、去泛素化并稳定其。此外，将 USP10 或 HDAC6 重新引入具有 null-p53 的 USP10 敲低 NSCLC H1299 细胞系中，可导致顺铂耐药。这一结果表明存在“USP10-HDAC6-顺铂耐药”轴。临床上，我们在一组 NSCLC 患者样本中发现了 USP10 和 HDAC6 表达之间的正相关。此外，我们表明，在接受铂类化疗的晚期 NSCLC 患者队列中，USP10 mRNA 水平高与总生存期差相关。总体而言，我们的研究表明，USP10 可能是预测患者对铂类药物反应的潜在生物标志物，并且靶向 USP10 可使缺乏野生型 p53 的肺癌患者对铂类药物治疗敏感。
