PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity

Abstract

Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is overexpressed in several malignancies. The newly identified protein posttranslational modification lactylation, occurring on lysine residues, is extensively involved in various biological processes. However, PD-L1 lactylation and its role in tumorigenesis remain unclear. In this study, we discover that lactylation of PD-L1 suppresses liver cancer growth by inhibiting cholesterol synthesis. Acetyltransferase E1A-binding protein p300 (p300) catalyzes the lactylation of PD-L1 at the lysine 189 residue (K189). Histone deacetylase 2-dependent delactylation of PD-L1 K189 promotes vimentin-mediated nuclear translocation of PD-L1. Functionally, PD-L1 K189 delactylation accelerates liver cancer growth both in vitro and in vivo by facilitating cholesterol production. Clinically, an antibody against PD-L1 K189 lactylation reveals that PD-L1 delactylation is positively associated with the progression of liver cancer histological grade. Mechanistically, PD-L1 K189 delactylation upregulates SQLE, a rate-limiting enzyme in cholesterol biosynthesis, by increasing SQLE transcription activity via the transcription factor YY1. Therefore, our findings demonstrate that lactylation-dependent regulation of PD-L1 promotes liver cancer growth.