CSN6 inhibition suppresses pancreatic adenocarcinoma metastasis via destabilizing the c-Fos protein

Abstract

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.