Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, China.
Department of General Surgery, Hunan Chest Hospital, Changsha 410006, China.
Exp Biol Med (Maywood). 2021 Sep;246(17):1869-1883. doi: 10.1177/15353702211023473. Epub 2021 Jun 25.
Pancreatic cancer is a highly malignant cancer of the pancreas with a very poor prognosis. Methylation of histone lysine residues is essential for regulating cancer physiology and pathophysiology, mediated by a set of methyltransferases (KMTs) and demethylases (KDMs). This study surveyed the expression of methylation regulators functioning at lysine 9 of histone 3 (H3K9) in pancreatic lesions and explored the underlying mechanisms. We analyzed KDM1A and KDM3A expression in clinical samples by immunohistochemical staining and searching the TCGA PAAD program and GEO datasets. Next, we identified the variation in tumor growth and after knockdown of KDM1A or KDM3A and explored the downstream regulators of KDM1A and KDM3A via RNA-seq, and gain- and loss-of-function assays. Eleven H3K9 methylation regulators were highly expressed in pancreatic cancer, and only KDM1A and KDM3A expression positively correlated with the clinicopathological characteristics in pancreatic cancer. High expression of KDM1A or KDM3A positively correlated with pathological grade, lymphatic metastasis, invasion, and clinical stage. Kaplan-Meier analysis indicated that a higher level of KDM1A or KDM3A led to a shorter survival period. Knockdown of KDM1A or KDM3A led to markedly impaired tumor growth and . Mechanistically, CCNA2, a cell cycle-associated gene was partially responsible for KDM1A knockdown-mediated effect and CDK6, also a cell cycle-associated gene was partially responsible for KDM3A knockdown-mediated effect on pancreatic cancer cells. Our study demonstrates that KDM1A and KDM3A are highly expressed in pancreatic cancer and are intimately correlated with clinicopathological factors and prognosis. The mechanism of action of KDM1A or KDM3A was both linked to the regulation of cell cycle-associated genes, such as CCNA2 or CDK6, respectively, by an H3K9-dependent pathway.
胰腺癌是一种高度恶性的胰腺肿瘤，预后极差。组蛋白赖氨酸残基的甲基化对于调节癌症的生理和病理生理学至关重要，这一过程由一组甲基转移酶（KMTs）和去甲基化酶（KDMs）介导。本研究调查了在胰腺病变中起作用的组蛋白 H3 赖氨酸 9 位（H3K9）甲基化调节因子的表达情况，并探讨了其潜在机制。我们通过免疫组织化学染色分析了临床样本中 KDM1A 和 KDM3A 的表达，并搜索了 TCGA PAAD 计划和 GEO 数据集。接下来，我们通过 RNA-seq 和 gain-和 loss-of-function 测定鉴定了敲低 KDM1A 或 KDM3A 后肿瘤生长的变化和下游调节因子。11 种 H3K9 甲基化调节因子在胰腺癌中高表达，只有 KDM1A 和 KDM3A 的表达与胰腺癌的临床病理特征呈正相关。KDM1A 或 KDM3A 高表达与病理分级、淋巴转移、侵袭和临床分期呈正相关。Kaplan-Meier 分析表明，较高水平的 KDM1A 或 KDM3A 导致较短的生存期。敲低 KDM1A 或 KDM3A 导致肿瘤生长显著受损和。从机制上讲，细胞周期相关基因 CCNA2 部分负责 KDM1A 敲低介导的效应，细胞周期相关基因 CDK6 部分负责 KDM3A 敲低对胰腺癌细胞的效应。本研究表明，KDM1A 和 KDM3A 在胰腺癌中高表达，并与临床病理因素和预后密切相关。KDM1A 或 KDM3A 的作用机制均与通过 H3K9 依赖性途径调节细胞周期相关基因（如 CCNA2 或 CDK6）有关。
