KAT2B-mediated epigenetic suppression of RAD51C enhances olaparib sensitivity in colorectal cancer.

INTRODUCTION: By blocking poly ADP ribose polymerase (PARP), olaparib decreases the proliferation of tumours by preventing DNA damage repair, particularly in tumours that have BRCA1/2 mutations or are BRCA-negative. However, a phase II study of 33 CRC patients receiving mono-olaparib therapy revealed that some of these individuals still had resistance to olaparib therapy but had poor DNA damage repair ability. RAD51C reversion mutation is a frequent reason for the resistance of cancers with BRCA mutations to PARP inhibitors. METHODS: Here, we introduce K(lysine)-acetyltransferase 2B (KAT2B) as a protein involved in the transcription of RAD51C, reducing the expression of RAD51C by lowering the acetylation of histone H3 (H3K27) at the promoter of RAD51C. RESULTS: We found that a subset of tumour cells expressing RAD51C presented reduced endogenous KAT2B expression, which led to increased accumulation of DNA damage (increased γH2AX accumulation), and lower KA2TB expression decreased PARPi resistance in RAD51C-expressing cells. These findings indicate that colorectal cancer cells with lower KAT2B and RAD51C levels are more vulnerable to olaparib therapy. Our findings indicate that PARPi responses and the expression of RAD51C are significantly regulated by KAT2B and histone acetylation. CONCLUSION: These results offer vital and novel insights into the combination of inhibitors in patients who are resistant to olaparib therapy, especially patients with RAD51C reversion mutations.