Inhibition of Histone Methyltransferase EZH2 for Immune-Interception of Colorectal Cancer in Lynch Syndrome

This study investigates the potential of EZH2 inhibition as a preventive strategy for colorectal cancer in Lynch Syndrome (LS) by modulating the immune system. Using a mouse model of LS and colonic organoids, researchers treated the mice with the EZH2 inhibitor GSK503 and observed increased CD4+ and CD8+ T cells in both spleen and colon tissue. Over a 9-week period, the inhibitor reduced adenoma formation, indicating its preventive efficacy. RNA sequencing and ChIPseq analyses revealed that EZH2 inhibition activated immune and apoptotic markers and decreased H3K27 methylation, leading to changes in gene regulation. These findings suggest that EZH2 inhibitors hold promise for cancer prevention in LS by reprogramming immune responses and gene expression patterns. A mouse model of LS colorectal carcinogenesis and ex vivo colonic organoids were utilized to assess the effects of an EZH2 inhibitor (GSK503) on regulatory pathways of adaptive immunity, tumorigenesis, and epigenetic reprogramming using RNA sequencing.