TGM2-mediated histone serotonylation promotes HCC progression via MYC signalling pathway.

Background & Aims: Hepatocellular carcinoma (HCC) is an aggressive malignancy for which there are few effective treatment options. H3Q5ser, a serotonin-based histone modification mediated by transglutaminase 2 (TGM2), affects diverse biological processes, such as neurodevelopment. The role of TGM2-mediated H3Q5ser in HCC progression remains unclear. This study investigated the role of TGM2 in promoting HCC progression and evaluated its potential as a therapeutic target for HCC treatment.

Methods: Adeno-associated virus-mediated liver-specific overexpression models of Tgm2 or H3.3 were adopted to validate the effects of H3Q5ser on HCC progression. CUT&Tag and RNA sequencing was employed to investigate the underlying mechanisms. HCC organoids, subcutaneous xenograft models, and hydrodynamic tail vein injection models were used to evaluate the treatment efficiency of TGM2 inhibitors.

Results: TMG2 expression positively correlated with higher alpha-fetoprotein levels, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably inhibited HCC progression. CUT&Tag and RNA sequencing analyses revealed that downregulated genes were enriched in the MYC pathway following treatment with TGM2 inhibitors. Furthermore, transcriptional intermediary factor 1 β mediated the recruitment of TGM2 to MYC, facilitating H3Q5ser modifications on MYC target genes. Finally, targeting the transglutaminase activity of TGM2 significantly suppressed HCC progression and showed synergy with sorafenib treatment in preclinical models. TGM2 inhibitors did not cause significant myelosuppression or tissue damage.

Conclusions: TGM2 serves as a prognostic biomarker and targeting its transglutaminase activity may be an effective strategy for inhibiting HCC progression.

Impact And Implications: Transglutaminase 2 (TGM2)-mediated H3Q5ser modifications promote hepatocellular carcinoma (HCC) progression via MYC pathway signalling. Targeting the transglutaminase activity of TGM2 markedly inhibited HCC progression. TGM2 inhibitors did not induce significant myelosuppression or tissue damage. This preclinical study provides a theoretical basis to explore new strategies for HCC therapy.