SET8是宫颈癌中一种频繁突变的基因，它通过损害DNA修复来增强顺铂敏感性。

SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair.

作者信息

Wang Xin, Cao Chen, Tan Xiangyu, Liao Xueyao, Du Xiaofang, Wang Xueqian, Liu Ting, Gong Danni, Hu Zheng, Tian Xun

机构信息

Department of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430014, China.

Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.

出版信息

Cell Biosci. 2023 Jun 12;13(1):107. doi: 10.1186/s13578-023-01054-y.

DOI:10.1186/s13578-023-01054-y

PMID:37308924

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10262521/

Abstract

BACKGROUND

Cisplatin is commonly used to treat cervical cancer while drug resistance limits its effectiveness. There is an urgent need to identify strategies that increase cisplatin sensitivity and improve the outcomes of chemotherapy.

RESULTS

We performed whole exome sequencing (WES) of 156 cervical cancer tissues to assess genomic features related to platinum-based chemoresistance. By using WES, we identified a frequently mutated locus SETD8 (7%), which was associated with drug sensitivity. Cell functional assays, in vivo xenografts tumor growth experiments, and survival analysis were used to investigate the functional significance and mechanism of chemosensitization after SETD8 downregulation. Knockdown of SETD8 increased the responsiveness of cervical cancer cells to cisplatin treatment. The mechanism is exerted by reduced binding of 53BP1 to DNA breaks and inhibition of the non-homologous end joining (NHEJ) repair pathway. In addition, SETD8 expression was positively correlated with resistance to cisplatin and negatively associated with the prognosis of cervical cancer patients. Further, UNC0379 as a small molecule inhibitor of SETD8 was found to enhance cisplatin sensitivity both in vitro and in vivo.

CONCLUSIONS

SETD8 was a promising therapeutic target to ameliorate cisplatin resistance and improve the efficacy of chemotherapy.

摘要

背景

顺铂常用于治疗宫颈癌，但其耐药性限制了其疗效。迫切需要确定提高顺铂敏感性并改善化疗效果的策略。

结果

我们对156例宫颈癌组织进行了全外显子组测序（WES），以评估与铂类化疗耐药相关的基因组特征。通过WES，我们鉴定出一个频繁突变的位点SETD8（7%），其与药物敏感性相关。采用细胞功能实验、体内异种移植肿瘤生长实验和生存分析来研究SETD8下调后化学增敏的功能意义和机制。敲低SETD8可增加宫颈癌细胞对顺铂治疗的反应性。其机制是通过减少53BP1与DNA断裂的结合并抑制非同源末端连接（NHEJ）修复途径来实现的。此外，SETD8的表达与顺铂耐药呈正相关，与宫颈癌患者的预后呈负相关。此外，发现作为SETD8小分子抑制剂的UNC0379在体外和体内均能增强顺铂敏感性。