Altieri Filomena, Di Stadio Chiara Stella, Federico Antonella, Miselli Giuseppina, De Palma Maurizio, Rippa Emilia, Arcari Paolo
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Hospital A. Cardarelli, Nasples, Italy.
Oncotarget. 2017 Mar 7;8(10):16899-16911. doi: 10.18632/oncotarget.14817.
The gastrokine 1 (GKN1) protein is important for maintaining the physiological function of the gastric mucosa. GKN1 is down-regulated in gastric tumor tissues and derived cell lines and its over-expression in gastric cancer cells induces apoptosis, suggesting a possible role for the protein as a tumor suppressor. However, the mechanism by which GKN1 is inactivated in gastric cancer remains unknown. Here, we investigated the causes of GKN1 silencing to determine if epigenetic mechanisms such as histonic modification could contribute to its down-regulation. To this end, chromatin immunoprecipitation assays for the trimethylation of histone 3 at lysine 9 (H3K9triMe) and its specific histone-lysine N-methyltransferase (SUV39H1) were performed on biopsies of normal and cancerous human gastric tissues. GKN1 down-regulation in gastric cancer tissues was shown to be associated with high levels of H3K9triMe and with the recruitment of SUV39H1 to the GKN1 promoter, suggesting the presence of an epigenetic transcriptional complex that negatively regulates GKN1 expression in gastric tumors. The inhibition of histone deacetylases with trichostatin A was also shown to increase GKN1 mRNA levels. Collectively, our results indicate that complex epigenetic machinery regulates GKN1 expression at the transcriptional level, and likely at the translational level.
胃动蛋白1（GKN1）蛋白对于维持胃黏膜的生理功能很重要。GKN1在胃肿瘤组织及其衍生的细胞系中表达下调，其在胃癌细胞中的过表达可诱导细胞凋亡，这表明该蛋白可能具有肿瘤抑制作用。然而，GKN1在胃癌中失活的机制尚不清楚。在此，我们研究了GKN1沉默的原因，以确定诸如组蛋白修饰等表观遗传机制是否有助于其下调。为此，我们对正常和癌性人胃组织活检样本进行了赖氨酸9处组蛋白3三甲基化（H3K9triMe）及其特异性组蛋白赖氨酸N - 甲基转移酶（SUV39H1）的染色质免疫沉淀试验。结果显示，胃癌组织中GKN1的下调与高水平的H3K9triMe以及SUV39H1募集到GKN1启动子有关，这表明存在一种表观遗传转录复合物，其对胃肿瘤中GKN1的表达起负调控作用。用曲古抑菌素A抑制组蛋白脱乙酰酶也显示可增加GKN1 mRNA水平。总体而言，我们的结果表明复杂的表观遗传机制在转录水平以及可能在翻译水平上调节GKN1的表达。
