Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
Pancreas. 2022 Feb 1;51(2):190-195. doi: 10.1097/MPA.0000000000001998.
Cigarette smoking is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). In this project, we investigated the effect of smoking and the role of histone deacetylase 4 (HDAC4) in PDAC invasion and metastasis.
Cells were treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and cigarette smoke extract and the mRNA levels of HDACs were measured by real-time polymerase chain reaction. Invasion was measured using the Matrigel Invasion Assay. Syngeneic PDAC mice were treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and metastasis measured. Human PDAC primary and metastatic tissues were analyzed by immunohistochemistry.
Levels of HDAC4 mRNA were increased by smoking. Smoking compounds significantly promoted invasion of cancer cells and promoted metastasis of PDAC cells to different organs, including the liver and the lung, whereas inhibition of HDAC4 prevented this effect. The effect of HDAC4 inhibition on preventing smoking-induced metastasis was greater in the liver compared with the lung. We found that HDAC4 is highly expressed in primary and metastatic PDAC tumors.
We found that HDAC4 is the only HDAC induced by smoking among all HDACs analyzed. We found that smoking promotes invasion and metastasis of PDAC cells through a mechanism that involves HDAC4 and that HDAC4 is a promising target for preventing PDAC metastasis.
吸烟是胰腺导管腺癌（PDAC）的既定危险因素。在本项目中，我们研究了吸烟的影响以及组蛋白去乙酰化酶 4（HDAC4）在 PDAC 侵袭和转移中的作用。
用 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮和香烟烟雾提取物处理细胞，并通过实时聚合酶链反应测量 HDAC 的 mRNA 水平。用 Matrigel 侵袭测定法测量侵袭。用 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮处理同源性 PDAC 小鼠，并测量转移。用人 PDAC 原发和转移组织进行免疫组织化学分析。
吸烟使 HDAC4 mRNA 水平升高。吸烟化合物显著促进癌细胞的侵袭，并促进 PDAC 细胞向不同器官转移，包括肝脏和肺部，而抑制 HDAC4 可防止这种作用。与肺相比，HDAC4 抑制对预防吸烟引起的转移的作用在肝中更大。我们发现 HDAC4 在原发性和转移性 PDAC 肿瘤中高度表达。
我们发现 HDAC4 是所有分析的 HDAC 中唯一由吸烟诱导的。我们发现吸烟通过涉及 HDAC4 的机制促进 PDAC 细胞的侵袭和转移，并且 HDAC4 是预防 PDAC 转移的有希望的靶标。
