SUMOylation of RAD51 upregulates GOLPH3 expression and promotes cisplatin resistance in colon cancer cells by Sp1 transcriptional activity

Abstract

Platinum-based chemotherapy is a first-line treatment for colon cancer. Previous studies have shown that Golgi phosphoprotein 3 (GOLPH3) overexpression drives platinum resistance in colon cancer and is associated with DNA damage repair (DDR). However, the mechanism by which DDR induces GOLPH3 expression remains unclear. This study investigates how RAD51 recombinase (RAD51) SUMOylation upregulates GOLPH3 expression and promotes platinum resistance in colon cancer. In DDP-resistant colon adenocarcinoma (COAD) cells, Specificity protein 1 (Sp1) and GOLPH3 were overexpressed, while N-myc downstream regulated 1 (NDRG1) was downregulated. Knockdown of Sp1 or GOLPH3 increased NDRG1 expression, inhibited COAD cell proliferation, promoted cell apoptosis, and enhanced cell sensitivity to cisplatin (DDP). Immunohistochemistry (IHC) and bioinformatics analyses of COAD tissues revealed a positive correlation between RAD51, SUMO1 and Sp1 expression. Sp1 was found to increase DDP resistance by transcriptionally activating GOLPH3 expression. RAD51 was SUMOylated by SUMO1 at the K57 site, and this modification decreased COAD cell sensitivity to DDP by enhancing Sp1 transcriptional activity. Furthermore, RAD51 overexpression led to upregulation of GOLPH3 and downregulation of NDRG1, promoting cell proliferation, inhibiting apoptosis, and increasing resistance to DDP. Conversely, the RAD51 mutant did not affect GOLPH3 expression or platinum resistance in vivo and in vitro. In conclusion, RAD51 SUMOylation at the K57 site enhances Sp1 transcriptional activity, thereby reducing colon cancer cell sensitivity to DDP by regulating GOLPH3 and NDRG1 expression. This discovery elucidates the molecular mechanism of DDR-induced GOLPH3 upregulation, offering a new perspective for overcoming DDP resistance in colon cancer.