ScholarWorks@성균관대학교

초록

5-Fluorouracil (5-FU) is afirst-line chemotherapy commonly used to treat colorectal cancer (CRC). However, the development ofacquired resistance to 5-FU remains a significant clinical challenge, and the underlying epigenetic mechanisms are not fullyunderstood. In this study, we demonstrate that euchromatic histone lysine methyltransferase 2 (EHMT2) is significantly upregulatedin CRC patients with poor responses to 5-FU, directly correlating with lower overall survival rates. Using established 5-FU resistant(5-FUR) HCT116 and HT29 cell lines, RNA-sequencing confirmed robust EHMT2 overexpression compared with wild-type cells.Mechanistically, siRNA-mediated knockdown of EHMT2 restored 5-FU sensitivity by upregulating protein phosphatase 1B (PPM1B),a key downstream target. This EHMT2-PPM1B axis disruption effectively induced G1 phase cell cycle arrest and triggered apoptosisin 5-FUR cells, fundamentally impairing their proliferation. Furthermore, we validated the therapeutic potential of targeting thispathway using in vivo and ex vivo models. Combination treatment with 5-FU and the specific pharmacological EHMT2 inhibitor(BIX-01294) synergistically suppressed tumor growth in a 5-FUR cell-derived xenograft mouse model. Importantly, these therapeuticeffects were faithfully recapitulated in 5-FUR patient-derived colorectal cancer organoid (PDO) models. Together, ourfindingselucidate a critical epigenetic mechanism where EHMT2 promotes 5-FU drug resistance. Targeting EHMT2 represents a promisingand translatable therapeutic strategy for overcoming chemoresistance and improving clinical outcomes in CRC patients.

키워드