Department of Environmental and Public Health Sciences, College of Medicine University of Cincinnati, 160 Panzeca Way, Cincinnati, OH, 45267, United States.
Division of Food and Biotechnology, College of Health and Life Sciences, Korea National University of Transportation, Jeungpyeong, Chungbuk, 27909, South Korea.
Biochem Biophys Res Commun. 2020 Nov 19;532(4):563-569. doi: 10.1016/j.bbrc.2020.08.053. Epub 2020 Sep 6.
Environmental toxicants such as dioxins and polycyclic aromatic carbons are risk factors for pancreatitis and pancreatic cancer. These toxicants activate aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, of which activation regulates many downstream biological events, including xenobiotic metabolism, inflammation, and cancer cell growth and transformation. Here, we identified that environmental toxicant-activated AHR increased expression of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in pancreatic cancer cells and pancreatic tissues. The MALAT1 is a long noncoding (lnc) RNA which interacts with Enhancer of Zeste 2 (EZH2), a histone methyltransferase with epigenetic silencer activity, and the MALAT1-EZH2 interaction increased its epigenetic silencing activity. In contrast, AHR antagonist, CH223191 or resveratrol, counteracted the AHR-mediated MALAT1 induction and MALAT1-enahnced EZH2 activity. Collectively, these results revealed a novel pathway of how environmental exposure leads to epigenetic alteration via activation of AHR-MALAT1-EZH2 signaling axis under pancreatic tissue- and cancer cell-context.
环境毒物，如二恶英和多环芳烃，是胰腺炎和胰腺癌的危险因素。这些毒物会激活芳烃受体（AHR），一种配体激活的转录因子，其激活调节许多下游生物学事件，包括外源性代谢物的代谢、炎症以及癌细胞的生长和转化。在这里，我们发现环境毒物激活的 AHR 会增加胰腺癌细胞和胰腺组织中转移相关肺腺癌转录本 1（MALAT1）的表达。MALAT1 是一种长链非编码（lnc）RNA，与 Enhancer of Zeste 2（EZH2）相互作用，EZH2 是一种具有表观遗传沉默活性的组蛋白甲基转移酶，而 MALAT1-EZH2 相互作用增加了其表观遗传沉默活性。相比之下，AHR 拮抗剂 CH223191 或白藜芦醇可拮抗 AHR 介导的 MALAT1 诱导和 MALAT1 增强的 EZH2 活性。总之，这些结果揭示了环境暴露如何通过激活 AHR-MALAT1-EZH2 信号轴，在胰腺组织和癌细胞背景下导致表观遗传改变的新途径。
