Related Experiment Video
Updated: Mar 15, 2026
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
KAT2B-mediated epigenetic suppression of RAD51C enhances olaparib sensitivity in colorectal cancer
Xiaoqin Liu1, Jun Chen2, Xuwei Shen3
1Department of Gastroenterology, Jingning People's Hospital, Lishui, JingNing, China.
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.
Insights
K(lysine)-acetyltransferase 2B (KAT2B) regulates RAD51C expression, impacting olaparib resistance in colorectal cancer. Lower KAT2B and RAD51C levels make tumors more vulnerable to PARP inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Olaparib, a PARP inhibitor, is effective against tumors with BRCA mutations but resistance occurs.
- RAD51C reversion mutations are a key cause of resistance to PARP inhibitors in BRCA-mutated cancers.
- Some colorectal cancer (CRC) patients exhibit resistance to olaparib despite poor DNA repair capacity.
Purpose of the Study:
- To investigate the role of K(lysine)-acetyltransferase 2B (KAT2B) in regulating RAD51C expression.
- To understand the mechanism by which KAT2B influences resistance to olaparib therapy in colorectal cancer.
- To identify potential therapeutic targets for overcoming olaparib resistance.
Main Methods:
- Investigated the transcriptional regulation of RAD51C by KAT2B.
- Assessed the effect of KAT2B on histone H3 (H3K27) acetylation at the RAD51C promoter.
- Correlated KAT2B and RAD51C expression levels with DNA damage markers (γH2AX) and olaparib response in CRC cells.
Main Results:
- Reduced endogenous KAT2B expression in RAD51C-expressing tumor cells led to increased DNA damage (γH2AX accumulation).
- Lower KAT2B expression decreased olaparib resistance in RAD51C-expressing cells.
- Colorectal cancer cells with lower KAT2B and RAD51C levels demonstrated increased vulnerability to olaparib therapy.
- PARP inhibitor response and RAD51C expression are significantly regulated by KAT2B and histone acetylation.
Conclusions:
- KAT2B plays a crucial role in regulating RAD51C expression and influencing olaparib sensitivity.
- Findings provide insights into overcoming olaparib resistance, particularly in patients with RAD51C reversion mutations.
- Suggests potential for combination therapies targeting KAT2B and PARP inhibitors for resistant cancers.
Related Concept Videos
02:23Abnormal Proliferation
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
02:37Restarting Stalled Replication Forks
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase