Macroscopic inhibition of DNA damage repair pathways by targeting AP-2 with LEI110 eradicates hepatocellular carcinoma

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-2 alpha 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-2 alpha inhibitor. Together, we demonstrate that LEI110 stabilizes AP-2 alpha and sensitizes HCC cells toward DNA-damaging reagents. Altogether, we identify AP-2 alpha as a crucial transcription modulator in HCC and propose small-molecule inhibitors targeting AP-2 alpha 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. In hepatocellular carcinoma, TFAP2A is a key player in the transcriptional regulation of a cluster of DNA damage repair genes: DNA repair is prevented by TFAP2A depletion, and the new TFAP2A inhibitor LEI110 shows anti-tumour efficacy in HCC cell lines.