ZEB1 promotes DNA homologous recombination repair and contributes to the 5-Fluorouracil resistance in colorectal cancer

Chemotherapy resistance represents a significant obstacle in clinical practice of colorectal cancer (CRC). In this study we aim to clarify the underlying mechanism of chemotherapy resistance mediated by ZEB1 in CRC. shRNA-mediated repression of ZEB1 induced DNA damage in SW480 and RKO cells. Ectopic expression of ZEB1 suppressed the DNA damage caused by ZEB1 knocking down in SW480 and RKO cells. In addition, ZEB1 directly targeted several DNA damage response (DDR) factors including NBS1, RNF8 and RNF168, and thereby the homologous recombination (HR) repair is mediated by ZEB1 via NBS1, RNF8 and RNF168 in CRC cells. Furthermore, ZEB1 maintained chromosome stability in CRC cells. By inducing NBS1, RNF8 and RNF168, ZEB1 is capable of promoting the 5-Fluorouracil (5-FU) resistance in CRC cells via enhancing the DDR signaling and DNA repair. The high expression of ZEB1, NBS1, RNF8 and RNF168 is associated with chemotherapy resistance in primary CRC patients. In conclusion, ZEB1 directly induces the expression of NBS1, RNF8 and RNF168, and thereby enhances DNA HR repair in CRC. The ZEB1-mediated DNA repair contributes to the 5-FU resistance in CRC.