Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers withBRCA1/2mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of theBRCA2gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain ofBRCA2may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.
奥拉帕尼通过抑制聚腺苷二磷酸核糖聚合酶（PARP）来抑制DNA损伤修复，尤其在携带BRCA1/2突变或具有BRCA样表型的癌症中效果显著。然而，初期临床试验显示部分DNA损伤修复功能缺陷的患者仍对奥拉帕尼产生耐药性。野生型BRCA功能恢复是BRCA缺陷肿瘤对PARP抑制剂（PARPi）耐药的重要机制，但奥拉帕尼耐药的其他分子特征尚不明确。本研究旨在探索结直肠癌（CRC）中影响奥拉帕尼应答或耐药的分子参数。我们发现组蛋白乙酰转移酶KAT2B通过降低结直肠癌BRCA2基因启动子区组蛋白H3第27位氨基酸（H3K27）的乙酰化水平，从而下调BRCA2表达。这一机制增强了CRC细胞对奥拉帕尼治疗的敏感性。BRCA2基因转录可能需要H3K27ac结合结构域的参与。我们在部分培养的BRCA2表达型CRC细胞中发现，内源性KAT2B低表达会导致γH2AX积累（表明DNA损伤增加），从而使BRCA2表达型细胞对PARPi耐药性降低。本研究揭示了KAT2B和组蛋白乙酰化作为BRCA2表达型CRC细胞中BRCA2表达及PARPi应答的调控因子，为靶向BRCA功能型肿瘤的分子先决条件提供了新的见解。
肿瘤(癌症)患者之家