Abstract
DNA damage repair (DDR) genes are known to be closely associated with the progression of Hepatocellular carcinoma (HCC). Here we report a unique cluster of "deletion-up" genes in HCC, which are accordantly overexpressed in HCC patients and predict the unfavorable prognosis. Binding motif analysis and further validation with ChIP-qPCR unveil that the AP-2α directly modulate the transcription of critical DNA repair genes including TOP2A, NUDT1, POLD1, and PARP1, which facilitates the sanitation of oxidized DNA lesions. Structural analysis and the following validation identify LEI110 as a potent AP-2α inhibitor. Together, we demonstrate that LEI110 stabilizes AP-2α and sensitizes HCC cells toward DNA-damaging reagents. Altogether, we identify AP-2α as a crucial transcription modulator in HCC and propose small-molecule inhibitors targeting AP-2α are a promising novel class of anticancer agents. Our study provides insights into the concept of macroscopic inhibition of DNA damage repair-related genes in cancer treatment.