USP18 and USP20 restrict oHSV-1 replication in resistant human oral squamous carcinoma cell line SCC9 and affect the viability of SCC9 cells

In this study, we discovered that two human oral squamous carcinoma cell (OSCC) lines, SCC9 and SCC25, exhibited varied levels of permissivity to oncolytic HSV-1 T1012G replication and the differential virus yields may associate with the constitutive accumulation of two deubiquitinating enzymes USP18 and USP20 in tumor cells. USP18 and USP20 belong to the ubiquitin-specific protease family, mediating the deubiquitination of targets and promoting antiviral responses. Depletion of USP18 or USP20 in SCC9 cells increased T1012G virus yields; overexpression of USP18 or USP20 in SCC25 cells down-regulated T1012G virus replication. In addition, STING as a verified substrate of USP18 and USP20, was found to affect the virus multiplication of T1012G in SCC9 cells. STING knockdown led to an increase in T1012G virus yields in SCC9 cells. Besides, we introduced a deubiquitinating enzyme inhibitor GSK2643943A targeting USP20 and evaluated its effects on viral replication and tumor killing in vitro and in vivo. The results showed that the combination of GSK2643934A and T1012G treatment brought a profound anti-tumor efficacy in mice bearing SCC9 tumors. This report explored factors that play roles in mediating oHSV-1 replication in OSCC tumor cells, facilitating to offer potential targets to improve oHSV-1 oncolytic efficacy and develop candidates of biomarkers to predict the efficiency of oHSV-1 multiplication in tumors.