Department of Oncology, Shanxian Central Hospital, Heze, Shandong, 274300, PR China.
Department of Oncology, Shanxian Haijiya Hospital, Heze, Shandong, 274300, PR China.
Exp Cell Res. 2020 Jun 1;391(1):112004. doi: 10.1016/j.yexcr.2020.112004. Epub 2020 Apr 11.
Deubiquitinase (DUB) can reverse the ubiquitin signal, and participate in virtually all aspects of cancer progression. Thus, DUB represents an attractive target for development of anticancer drugs. However, little is known about DUB which can be used as drug targets. Here, we found that the constitutive photomorphogenic 9 (COP9) signalosome complex subunit 6 (COPS6/CSN6), a DUB belongs to JAMM/MPN domain-associated metallopeptidases(JAMMs) class, was highly expressed in pancreatic adenocarcinoma(PAAD) tissues. High expression of CSN6 was associated with tumor TNM stage and metastasis in PAAD patients. Moreover, we demonstrated that CSN6 promoted invasion and metastasis through regulating forkhead box protein A1 (FOXA1) in PAAD cells. Re-expression of FOXA1 rescued the decreased invasion and metastasis caused by CSN6 knockdown, whereas inhibition of FOXA1 alleviated the pro-metastasis effect induced by CSN6 overexpression. Further, CSN6 regulated the expression of FOXA1 via c-Fos in PAAD cells. Mechanistically, CSN6 stabilized c-Fos protein by binding to it and decreasing its ubiquitination. Our work identified CSN6 as a targeting-permissible deubiquitinase, and CSN6 inhibition maybe a potential treatment strategy for PAAD.
去泛素化酶（DUB）可以逆转泛素信号，参与癌症进展的几乎所有方面。因此，DUB 代表了开发抗癌药物的有吸引力的靶点。然而，人们对可作为药物靶点的 DUB 知之甚少。在这里，我们发现组成型光形态发生 9（COP9）信号小体复合物亚基 6（COPS6/CSN6），一种属于 JAMM/MPN 结构域相关金属肽酶（JAMMs）类的 DUB，在胰腺导管腺癌（PAAD）组织中高度表达。CSN6 的高表达与 PAAD 患者的肿瘤 TNM 分期和转移有关。此外，我们证明 CSN6 通过调节叉头框蛋白 A1（FOXA1）在 PAAD 细胞中促进侵袭和转移。FOXA1 的重新表达挽救了 CSN6 敲低引起的侵袭和转移减少，而 FOXA1 的抑制减轻了 CSN6 过表达诱导的促转移作用。此外，CSN6 通过 c-Fos 在 PAAD 细胞中调节 FOXA1 的表达。在机制上，CSN6 通过与 c-Fos 结合并减少其泛素化来稳定 c-Fos 蛋白。我们的工作确定 CSN6 为一种可靶向的去泛素化酶，CSN6 抑制可能是 PAAD 的一种潜在治疗策略。
