Macroscopic inhibition of DNA damage repair pathways by targeting TFAP2A with LEI110 eradicates hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is one of the world’s leading causes of cancer-related death and DNA damage repair-related genes were closed related to the progression of HCC. Combining the copy number variation and the expression profile of DNA damage repair-related genes, we observed a unique cluster of “deletion-up” genes in HCC, which strongly correlated with the prognosis of liver cancer. Binding motif analysis and further validation with ChIP-qPCR/dual luciferase assay unveiled that the TFAP2A could modulate the transcription of critical DNA repair genes including TOP2A, NUDT1, POLD1, and PARP1, which eventually facilitated the sanitation of oxidized DNA lesions in cells. Structural analysis and the following validation identified LEI110 as a potent TFAP2A inhibitor. We demonstrated that LEI110 could stabilize TFAP2A and sensitize HCC cells towards different DNA damaging reagents in liver cancer cells. Together, we identified TFAP2A as a crucial transcription modulator for a unique cluster of “deletion-up” genes in HCC and identified LEI110 as a potential inhibitor of TFAP2A which sensitized HCC to DNA-damaging reagents. Our study provide insights into a concept of macroscopic inhibition of DNA damage repair-related genes in the cancer treatment.