PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair

Abstract

Background Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer; however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to explore the role of PRDM15 involved in the radioresistance of colorectal cancer and to clarify the underlying mechanism. Methods The expression and localization of PRDM15 was measured with Western blot and immunofluorescence assay. Lenti-virus was applied to perform knockdown or overexpression of PRDM15. Colorectal cancer cells exposed to γ-rays were assayed by DNA damage, cytotoxicity, apoptosis and cell cycle. Moreover, DNA damage response was detected and immunoprecipitation was used to explore protein interactions. The potent role of PRDM15 in overcoming radioresistance was investigated in CDX and PDX models. Finally, the correlation between PRDM15 expression and clinical outcomes were investigated in 80 locally advanced rectal cancer patients receiving neoadjuvant chemoradiotherapy. Results After DNA damage, PRDM15 was upregulated and localized to DNA damage sites, colocalized with γH2AX. Knockdown of PRDM15 inhibited DNA damage repair and increased radiosensitivity in colorectal cancer cells. Mechanistically, PRDM15 promoted DNA repair by interacting with DNA-PKcs and Ku70/Ku80 complex. Knockdown of PRDM15 sensitized CDX and PDX models to radiotherapy. Higher PRDM15 expression in cancer tissue was associated with inferior tumor regression and poorer prognosis in colorectal cancer patients treated with neoadjuvant chemoradiotherapy. Conclusions Our findings revealed that inhibiting PRDM15 was potent to overcome radioresistance through abrogating DNA repair in colorectal cancer cells. Additionally, the expression level of PRDM15 could be applied to predict radiotherapy responsiveness in rectal cancer patients.