Ubiquitin specific peptidase 32 acts as an oncogene in epithelial ovarian cancer by deubiquitylating farnesyl-diphosphate farnesyltransferase 1
Ubiquitin specific peptidase 32 acts as an oncogene in epithelial ovarian cancer by deubiquitylating farnesyl-diphosphate farnesyltransferase 1
复制标题
DOI：
10.1016/j.bbrc.2021.03.049
复制
发表时间：
2021-03-18
影响因子：
3.1
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
--
作者：
Nakae, Aya;Kodama, Michiko;Kimura, Tadashi
上皮性卵巢癌（Epithelial ovarian cancer，EOC）是世界上第七大常见癌症，也是最致命的妇科恶性肿瘤，因为其侵袭性和高复发率。为了发现EOC的新治疗靶点，我们将公开的EOC微阵列数据集与我们之前的体内shRNA筛选数据集相结合。排名第一的基因泛素特异性肽酶32（USP 32），编码去泛素化酶，是泛素蛋白酶体系统的一个组成部分。临床上，USP 32在原发性卵巢癌中表达，特别是在转移性腹膜肿瘤中，并对生存结果产生负面影响。USP 32调节与EOC进展相关的增殖和上皮间质转化能力。蛋白质组学分析确定法尼基-二磷酸法尼基转移酶1（FDFT 1）是USP 32的一种新型底物，USP 32是甲羟戊酸途径中的一种酶，基本上与细胞增殖和干性相关。USP 32和FDFT 1在肿瘤球中的表达高于贴壁细胞。抑制USP 32、FDFT 1或甲羟戊酸途径可显著抑制肿瘤球形成，并可通过添加FDFT 1的下游产物角鲨烯恢复。这些结果表明，USP 32-FDFT 1轴有助于EOC的进展，并可能成为EOC治疗的新靶点。(c)2021爱思唯尔公司卵巢上皮癌（EOC）是世界上第七大常见癌症，也是最致命的妇科恶性肿瘤，因为它的侵袭性和高复发率。为了发现EOC的新治疗靶点，我们将公开的EOC微阵列数据集与我们之前的体内shRNA筛选数据集相结合。排名第一的基因泛素特异性肽酶32（USP 32），编码去泛素化酶，是泛素蛋白酶体系统的一个组成部分。临床上，USP 32在原发性卵巢癌中表达，特别是在转移性腹膜肿瘤中，并对生存结果产生负面影响。USP 32调节与EOC进展相关的增殖和上皮间质转化能力。蛋白质组学分析确定法尼基-二磷酸法尼基转移酶1（FDFT 1）是USP 32的一种新型底物，USP 32是甲羟戊酸途径中的一种酶，基本上与细胞增殖和干性相关。USP 32和FDFT 1在肿瘤球中的表达高于贴壁细胞。抑制USP 32、FDFT 1或甲羟戊酸途径可显著抑制肿瘤球形成，并可通过添加FDFT 1的下游产物角鲨烯恢复。这些结果表明，USP 32-FDFT 1轴有助于EOC的进展，并可能成为EOC治疗的新靶点。
Epithelial ovarian cancer (EOC) is the seventh most common cancer worldwide and the deadliest gynecological malignancy because of its aggressiveness and high recurrence rate. To discover new therapeutic targets for EOC, we combined public EOC microarray datasets with our previous in vivo shRNA screening dataset. The top-ranked gene ubiquitin specific peptidase 32 (USP32), coding a deubiquitinating enzyme, is a component of the ubiquitin proteasome system. Clinically, USP32 is expressed in primary ovarian cancer, especially in metastatic peritoneal tumors, and negatively impacts the survival outcome. USP32 regulates proliferative and epithelial mesenchymal transition capacities that are associated with EOC progression. Proteomic analysis identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as a novel substrate of USP32 that is an enzyme in the mevalonate pathway, essentially associated with cell proliferation and stemness. USP32 and FDFT1 expression was higher in tumor spheres than in adherent cells. Inhibition of USP32, FDFT1, or mevalonate pathway considerably suppressed tumor sphere formation, which was restored by adding squalene, a downstream product of FDFT1. These findings suggested that USP32-FDFT1 axis contributes to EOC progression, and could be novel therapeutic targets for EOC treatment.(c) 2021 Elsevier Inc. All rights reserved.Epithelial ovarian cancer (EOC) is the seventh most common cancer worldwide and the deadliest gynecological malignancy because of its aggressiveness and high recurrence rate. To discover new therapeutic targets for EOC, we combined public EOC microarray datasets with our previous in vivo shRNA screening dataset. The top-ranked gene ubiquitin specific peptidase 32 (USP32), coding a deubiquitinating enzyme, is a component of the ubiquitin proteasome system. Clinically, USP32 is expressed in primary ovarian cancer, especially in metastatic peritoneal tumors, and negatively impacts the survival outcome. USP32 regulates proliferative and epithelial mesenchymal transition capacities that are associated with EOC progression. Proteomic analysis identified farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as a novel substrate of USP32 that is an enzyme in the mevalonate pathway, essentially associated with cell proliferation and stemness. USP32 and FDFT1 expression was higher in tumor spheres than in adherent cells. Inhibition of USP32, FDFT1, or mevalonate pathway considerably suppressed tumor sphere formation, which was restored by adding squalene, a downstream product of FDFT1. These findings suggested that USP32-FDFT1 axis contributes to EOC progression, and could be novel therapeutic targets for EOC treatment.