Investigating the function of EHMT2 in regulating gastrointestinal cancer progression

Abstract

Colorectal cancer and gastric cancer are cancers with high incidence and mortality rates worldwide. Although surgical and chemical therapies are commonly used, there is still a need for research on effective therapeutic targets. Recent studies demonstrated that EHMT2, a histone methyltransferase, plays a role in the proliferation and metastasis of various cancers, including breast cancer, liver cancer, and lung cancer. In this study, we confirmed that propionate, a metabolite of gut microbiota, induces apoptosis of colorectal cancer cells. We revealed that the induction of apoptosis by propionate is mediated by the degradation of EHMT2, which is highly expressed in colon cancer, through poly-ubiquitination induced by the upregulation of HECTD2, an E3 ubiquitin ligase. We also showed that the inhibition of EHMT2 directly increases the expression of TNFAIP1, leading to apoptosis of colorectal cancer cells. In addition, we found that inhibiting EHMT2, which is highly expressed in gastric cancer, induces G1 cell cycle arrest and inhibits the growth of gastric cancer cells by increasing the expression of TP53INP1, a direct target gene of EHMT2. We confirmed this effect using 3D culture system and patient-derived gastric cancer organoids. Therefore, we suggest that EHMT2 can be an effective target for the treatment of colorectal and gastric cancers.