Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by modulating cell cycle and apoptosis
Summary
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 apoptosis in 5-FUR cells, fundamentally impairing their proliferation. Furthermore, we validated the therapeutic potential of targeting th
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# Targeting EHMT2 overcomes 5-fluorouracil resistance in colorectal cancer by modulating cell cycle and apoptosis
*Published: 2026 May 18*
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 apoptosis in 5-FUR cells, fundamentally
impairing their proliferation. Furthermore, we validated the therapeutic
potential of targeting this pathway 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 therapeutic effects were faithfully
recapitulated in 5-FUR patient-derived colorectal cancer organoid (PDO) models.
Together, our findings elucidate a critical epigenetic mechanism where EHMT2
promotes 5-FU drug resistance. Targeting EHMT2 represents a promising and
translatable therapeutic strategy for overcoming chemoresistance and improving
clinical outcomes in CRC patients.
DOI: 10.1038/s41392-026-02692-7