The SUMOylated RREB1 interacts with KDM1A to induce 5‐fluorouracil resistance via upregulating thymidylate synthase and activating DNA damage response pathway in colorectal cancer

Chemoresistance is one main cause of failure in colorectal cancer (CRC) treatment. The role of transcription factor Ras-responsive element binding protein 1 (RREB1) remains unclarified in CRC chemoresistance. Herein, we reveal that RREB1 functions as an oncogene to promote cell proliferation and 5-fluorouracil (5-FU) chemoresistance in CRC, and SUMOylation is required for RREB1 to exert its oncogenic role in CRC. RREB1 induced cell cycle arrest at the S-phase and a decreased apoptosis rate under 5-FU exposure. Mechanistically, the interaction of RREB1 with lysine demethylase 1A (KDM1A) elevated expression of 5-FU targeting proteins thymidylate synthase (TS) and thymidine kinase (TK1) to maintain the nucleotide pool balance under 5-FU treatment, and enhanced activation of Chk1-mediated DNA damage response (DDR) pathway. The deSUMOylation of RREB1 resulted in a reduced interaction of RREB1 with KDM1A, contributing to a downregulation of TS expression and a less activation of DDR pathway. Moreover, KDM1A knockdown improved the DNA damage and reduced RREB1-mediated resistance to 5-FU. These findings provide new insights into RREB1-mediated chemotherapy responses in CRC and indicate RREB1 is a potential target for overcoming 5-FU resistance.