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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• DNA damage repair (DDR) genes are implicated in Hepatocellular carcinoma (HCC) progression.
• A specific group of "deletion-up" genes are overexpressed in HCC, correlating with poor prognosis.

Purpose of the Study:

• To investigate the role of AP-2α in regulating DDR genes in HCC.
• To identify and validate inhibitors of AP-2α for potential HCC therapy.

Main Methods:

• Binding motif analysis and ChIP-qPCR to determine AP-2α's transcriptional modulation.
• Structural analysis and validation to identify AP-2α inhibitors.
• Assessment of LEI110's effect on AP-2α stability and HCC cell sensitivity to DNA-damaging agents.

Main Results:

• AP-2α directly upregulates critical DDR genes (TOP2A, NUDT1, POLD1, PARP1), aiding oxidized DNA lesion repair.
• LEI110 identified as a potent AP-2α inhibitor that stabilizes AP-2α.
• LEI110 treatment sensitizes HCC cells to DNA-damaging agents.

Conclusions:

• AP-2α is a key transcription modulator in HCC, promoting DNA repair.
• Targeting AP-2α with small-molecule inhibitors like LEI110 represents a promising therapeutic strategy for HCC.
• Macroscopic inhibition of DDR-related genes offers novel insights for cancer treatment.