KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells.
KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells.
复制标题
KAT8/MOF介导的吉西他滨对人膀胱癌细胞的抗癌机制
DOI：
10.4062/biomolther.2020.111
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发表时间：
2021-03-01
影响因子：
3.7
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Zhu H;Wang Y;Wei T;Zhao X;Li F;Li Y;Wang F;Cai Y;Jin J
组蛋白乙酰化是由组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）控制的表观遗传修饰。在许多原发性癌症中已经观察到不平衡的组蛋白乙酰化。因此，人们一直在努力寻找药物或小分子，如HDAC抑制剂，可以使癌细胞中的乙酰化水平恢复正常。我们观察到KAT 8（也称为人MOF）的内源性和外源性蛋白表达水平呈剂量依赖性降低，KAT 8是MYST家族HAT的成员，在化疗药物吉西他滨（GEM）暴露的T24膀胱癌（BLCA）细胞中，其相应的组蛋白乙酰化位点为H4 K5、H4 K8和H4 K16。有趣的是，MOF和组蛋白H4乙酰化的减少与GEM诱导的γ H2 AX成反比，γ H2 AX是化疗药物有效性的指标。此外，GEM显著抑制pGL 4-MOF-Luc报告基因活性，从而表明GEM利用了MOF介导的抗BLCA作用机制。在CCK-8、伤口愈合测定和实验中，在外源性MOF和GEM存在下观察到对细胞增殖和迁移的累加效应。此外，使用Annexin V-FITC/PI测定证实了BLCA细胞中外源性MOF促进的细胞对GEM的敏感性。以上结果为阐明GEM抗BLCA的作用机制提供了理论依据。
Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.