Role of Trichostatin A (TSA) in modulating the epigenetic modification in the lymphocytes of colorectal cancer (CRC).

Trichostatin A (TSA) is a strong epigenetic tool that promises to have the future in the field of immune reprogramming, but its mechanisms of action in patient-derived immune cells in colorectal cancer (CRC) are still poorly studied. We examined in this current study the molecular and functional immune phenotype of lymphocytes of CRC patients and healthy donors in response to low-dose (0.1 nM), short-term (12 h) treatment with TSA, which aims at narrowing cytotoxicity and retaining epigenetic regulation. The TSA potentiated pro-inflammatory cytokines (IFN-gamma, IL-12, TNF-alpha) and inhibited immunoregulatory interleukins (IL-4, IL-10, IL-17, CCL5, Granzyme B in CRC-derived immune cells). At the transcriptional level, TSA induced TBX21 and TP53 and repressed GATA3, FOXP3, RORC, and MYC. Epigenetic profiling showed H3K14ac and H3K4me3 markups, H3K27me3 and HDAC1 downregulation, promoter hypermethylation of immune territory, less R-loop formation, and higher methylation of m6A RNA-partaking in the recommendation that TSA promotes chromatin and transcriptome multilayered modification. The TSA pretreated lymphocytes elicited cytotoxic effect in HT-29 CRC cells and also showed redox disproportion via depletion of glutathione and increase in nitric oxide. Although previous research focuses on the direct impact of TSA on tumor cells, in our study, we exclusively highlight TSA ability to reprogram the immune cells epigenetically in a more inflammatory tumor-reactive phenotype. The findings justify the possibility of TSA as an epigenetic adjunct of low toxicity in immuno-oncology and form a basis to continue in vivo and translational study in CRC immunotherapy.