Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation.
Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation.
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Fisetin 通过 RFXAP/KDM4A 依赖性组蛋白 H3K36 去甲基化诱导 DNA 损伤来抑制胰腺腺癌的增殖
DOI：
10.1038/s41419-020-03019-2
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发表时间：
2020-10-22
影响因子：
9
通讯作者：
Cao L
中科院分区：
文献类型：
--
作者：
Ding G;Xu X;Li D;Chen Y;Wang W;Ping D;Jia S;Cao L
胰腺癌(PDAC)是一种与低生存率相关的恶性程度极高的肿瘤。非瑟酮是一种天然黄酮类化合物，在各种癌症中显示出包括DNA损伤在内的多种抗肿瘤作用。越来越多的研究表明，表观遗传修饰在DNA损伤反应中起着关键作用。然而，非瑟素在癌症中的表观遗传调控机制却鲜有研究。RFXAP是MHC II分子的关键转录因子，但其在PDAC中的转录作用尚不清楚。采用CCK-8、流式细胞仪、裸鼠移植瘤模型检测Fisetin的抗PDAC作用。用免疫荧光法检测DNA损伤水平。生物信息学分析检测RFXAP等参与DNA损伤反应的基因的表达。用芯片测序方法研究RFXAP的转录作用。用qRT-PCR和Western blotting检测目的基因KDM4A的表达，用双荧光素酶报告基因分析KDM4A启动子活性。通过RFXAP过表达或沉默PDAC细胞的方法，探讨RFXAP对Fesetin诱导的DNA损伤的影响。我们发现菲斯汀能抑制细胞增殖，引起细胞DNA损伤和S期阻滞。Fisetin上调了RFXAP等DNA损伤反应基因的表达。我们发现，RFXAP在PDAC中的表达相对较低，并与肿瘤分期和预后不良有关。然后我们研究了RFXAP的转录作用，发现RFXAP靶向KDM4A，一种专用于三甲基化和二甲基化组蛋白H3K36的去甲基酶。我们发现，RFXAP的过表达上调了KDM4A，减弱了H3K36的甲基化，从而损害了DNA修复，增强了Fesetin诱导的DNA损伤，而RFXAP的沉默则表现出相反的作用。我们还发现了非瑟素在增强胰腺癌细胞化疗效果方面的作用。我们的结果表明，非瑟素通过依赖RFXAP/KDM4A的组蛋白H3K36去甲基化诱导DNA损伤，从而抑制PDAC的增殖。
Pancreatic adenocarcinoma (PDAC) is an extremely malignant tumor that is associated with low survival rates. Fisetin is a natural flavonoid that shows diverse antitumor effects, including DNA damage, in various cancers. Increasing studies have demonstrated that epigenetic modifications play critical roles in DNA-damage response. However, the epigenetic regulation mechanism of fisetin in cancers is hardly studied. RFXAP is a critical transcription factor for MHC II molecules, however, its transcriptional role in PDAC is poorly understood. The anti-PDAC effect of fisetin was measured by CCK-8, flow cytometry, xenograft tumor nude mice model. DNA-damage levels were examined by immunofluorescence. Bioinformatics analysis was used to examine the expression of RFXAP and other genes involved in DNA-damage response. ChIP sequencing was used to explore the transcriptional role of RFXAP. The expression of target geneKDM4Awas measured by qRT-PCR and western blots.KDM4Apromoter activity was analyzed using dual-luciferase reporter assay. RFXAP overexpressing or silencing of PDAC cells was used to explore the effect of RFXAP in DNA damage induced by fisetin. We found that fisetin inhibited cell proliferation and induced DNA damage and S-phase arrest in PDAC. Expression ofRFXAPand other DNA-damage response genes were upregulated by fisetin. We revealed thatRFXAPexpression was relatively low in PDAC and correlated with tumor stage and poor prognosis. Then we explored the transcriptional role of RFXAP and found that RFXAP targetedKDM4A, a special demethylase specific for tri- and dimethylated histone H3K36. We found that overexpression of RFXAP upregulatedKDM4Aand attenuated methylation of H3K36, thereby impairing DNA repair and enhancing the DNA damage induced by fisetin, whileRFXAPsilencing showed the opposite effect. We also found the function of fisetin in enhancing the effect of chemotherapy on pancreatic cancer cells. Our findings revealed that fisetin induced DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation, thus causing inhibition of proliferation in PDAC.
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影响因子：
64.5
作者：
Buis J;Wu Y;Deng Y;Leddon J;Westfield G;Eckersdorff M;Sekiguchi JM;Chang S;Ferguson DO
通讯作者：
Ferguson DO
影响因子：
--
作者：
Ding G;Zhou L;Qian Y;Fu M;Chen J;Chen J;Xiang J;Wu Z;Jiang G;Cao L
通讯作者：
Cao L
影响因子：
5.7
作者：
Al Abo M;Sasanuma H;Liu X;Rajapakse VN;Huang SY;Kiselev E;Takeda S;Plunkett W;Pommier Y
通讯作者：
Pommier Y
影响因子：
6.4
作者：
Fan, Cong;Zhang, Juan;Xie, Yuntao
通讯作者：
Xie, Yuntao
影响因子：
16.8
作者：
Daugaard, Mads;Baude, Annika;Jaattela, Marja
通讯作者：
Jaattela, Marja