Luteolin reverses chemoresistance in colorectal cancer cells via TET1/TDG-dependent epigenetic repression of β-catenin.

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXT) remains a major cause of treatment failure in colorectal cancer (CRC). Luteolin, a dietary flavonoid with anticancer properties, has shown therapeutic potential in various malignancies, but its effects on chemotherapy-resistant CRC remain poorly understood. In this study, we investigated whether luteolin restores chemosensitivity in 5-FU-resistant (SNUC5/5-FUR) and OXT-resistant (SNUC5/OXTR) CRC cells and explored the underlying molecular mechanisms. Luteolin reduced cell viability and induced apoptosis in both resistant cell lines. Mechanistically, luteolin suppressed β-catenin expression by downregulating ten-eleven translocation (TET) proteins, increasing DNA methyltransferase (DNMT) expression, enhancing CpG methylation, and reducing TET1 occupancy at the β-catenin promoter. Luteolin also decreased thymine DNA glycosylase (TDG) expression, disrupted the TET1/TDG interaction, and reduced TDG recruitment to the β-catenin promoter. Consistently, knockdown of either TET1 or TDG decreased β-catenin expression, while luteolin further enhanced apoptosis in siTET1-or siTDG-transfected resistant cells. Additionally, luteolin attenuated intracellular reactive oxygen species accumulation and potentiated the cytotoxic effects of 5-FU and OXT in resistant CRC cells. These findings demonstrate that luteolin reverses chemoresistance by suppressing the TET1/TDG-β-catenin axis through epigenetic regulation and modulation of intracellular redox homeostasis, supporting its potential as an adjuvant for CRC chemotherapy.