Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.
Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.
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DOI：
10.18632/oncotarget.13572
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Donahue TR
中科院分区：
文献类型：
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作者：
Nguyen AH;Elliott IA;Wu N;Matsumura C;Vogelauer M;Attar N;Dann A;Ghukasyan R;Toste PA;Patel SG;Williams JL;Li L;Dawson DW;Radu C;Kurdistani SK;Donahue TR
虽然组蛋白去乙酰化酶抑制剂（HDACi）是一类很有前途的抗癌药物，但迄今为止，它们在胰腺导管腺癌（PDAC）的早期临床试验中并不成功。其疗效差的一个潜在原因是肿瘤基质，其中癌症相关成纤维细胞（CAF）是一种突出的细胞类型，也是对癌症治疗产生耐药性的来源。在这里，我们证明了基质成纤维细胞有助于HDACi在PDAC中的不良功效。HDACi处理的成纤维细胞显示出增加的生物侵袭性，并且特征在于促炎性肿瘤支持性细胞因子和趋化因子的分泌增加。我们发现HDAC 2与CAFs中促炎基因的增强子和启动子区域特异性结合，并且计算机分析鉴定AP-1是与这些区域结合最频繁的相关转录因子。AP-1上游通路的药理学抑制抑制HDACi诱导的成纤维细胞中的炎症基因表达和肿瘤支持反应。我们的研究结果表明，HDACi与AP-1信号传导途径的化学抑制剂的组合减弱了成纤维细胞的炎性表型，并可能改善HDACi在PDAC中的功效，并可能改善在其他富含基质的实体瘤中的功效。
Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.