TGM2-mediated histone serotonylation promotes HCC progression via MYC signalling pathway [RNA-Seq]

Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models. Mechanistic study of TGM2 inhibition with GK921 exposes drug targetable vulnerabilities in HCC. MHCC-97H cells were exposed to DMSO and/or GK921 (2μM). Following 24 hours exposure, RNA was extracted from these cells and then subjected to RNA sequence analysis.