RBM30 recruits DOT1L to activate STAT1 transcription and drive immune evasion in hepatocellular carcinoma
Hexu Han, Gong Chen, Yue Zhang, Cuixia Liu, Yifan Wang, Dakun Zhao, Junxing Huang, Zhicheng Gong
Abstract
Programmed death ligand 1 (PD-L1) is a protein expressed in hepatocellular carcinoma (HCC) that drives immune evasion by binding to programmed death receptor 1 (PD-1) on activated T cells. Understanding PD-L1 regulation is essential to understand the immunosuppressive microenvironment for antitumor immunity. We screened ribonucleic acid (RNA)-binding motif proteins (RBMs). RBM30 can enhance PD-L1 expression in HCC cells. In this study, we found that high RBM30 expression in tumor tissues can drive HCC tumor immune evasion and accelerate disease progression via increased PD-L1 transcription. We conducted multiple molecular and high-throughput assays to elucidate the intrinsic molecular mechanisms by which RBM30 upregulates PD-L1 expression in HCC. RBM30 binds to DNA near the transcriptional start site of STAT1 and recruits DOT1L to promote H3K79me3 enrichment, enhancing its accessibility to upregulate STAT1 transcription, consequently activating the PD-L1 transcription. This enhances PD-L1 expression to facilitate immune evasion. These findings reveal the vital role of RBM30 in HCC immune evasion.