The mutual regulation of SOX12 and RNF168 modulates cisplatin resistance in esophageal squamous cell carcinoma cells by regulating DNA damage repair.

Resistance to chemotherapy drugs is one of the significant factors for limited treatment options and poor prognosis in esophageal cancer. A study has found that SOX12 plays a role in cisplatin resistance in hepatocellular carcinoma cells, but the function and mechanism of SOX12 in cisplatin resistance in esophageal cancer are unclear. Our study found that SOX12 protein levels are significantly elevated in cisplatin-resistant esophageal cancer cell lines and in esophageal cancer cells treated with cisplatin. Knocking down SOX12 enhances the sensitivity of esophageal cancer cells to cisplatin. Additionally, we have observed that elevated SOX12 protein promotes the efficiency of DNA double-strand break repair. Mechanistically, we found that the depletion of SOX12 results in a notable reduction in the levels of RNF168 protein, while its mRNA expression remains unaffected. Furthermore, we demonstrated that SOX12 regulates RNF168 protein stability by transcriptionally repressing the expression of TRIP12 and UBR5. On the other hand, we have also discovered that RNF168 interacts with and stabilizes SOX12 protein via a ubiquitin-proteasome system. Collectively, our study identifies a feedback regulatory loop between SOX12 and RNF168 that promotes DNA damage repair and cisplatin resistance in esophageal cancer cells.