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Abstract：
Salivary gland tumors (SGTs) are rare and complex neoplasms characterized by heterogenous histology and clinical behavior as well as resistance to systemic therapy. Tumor etiology is currently under elucidation and an interplay of genetic and epigenetic changes has been proposed to contribute to tumor development. In this work, we investigated epigenetic regulators and histone-modifying factors that may alter gene expression and participate in the pathogenesis of SGT neoplasms. We performed a detailed bioinformatic analysis on a publicly available RNA-seq dataset of 94 ACC tissues supplemented with clinical data and respective controls and generated a protein-protein interaction (PPI) network of chromatin and histone modification factors. A significant upregulation of TP53 and histone-modifying enzymes SUV39H1, EZH2, PRMT1, HDAC8, and KDM5B, along with the upregulation of DNA methyltransferase DNMT3A and ubiquitin ligase UHRF1 mRNA levels, as well as a downregulation of lysine acetyltransferase KAT2B levels, were detected in ACC tissues. The protein expression of p53, SUV39H1, EZH2, and HDAC8 was further validated in SGT tissues along with their functional deposition of the repressive histone marks H3K9me3 and H3K27me3, respectively. Overall, this study is the first to detect a network of interacting proteins affecting chromatin structure and histone modifications in salivary gland tumor cells, further providing mechanistic insights in the molecular profile of SGTs that confer to altered gene expression programs.
摘要：
涎腺肿瘤（SGT）是一种罕见且复杂的肿瘤，其特征是组织学和临床行为异质性以及对全身治疗的抵抗力。目前正在阐明肿瘤的病因，并且已经提出遗传和表观遗传变化的相互作用有助于肿瘤的发展。在这项工作中,我们研究了可能改变基因表达并参与SGT肿瘤发病机制的表观遗传调节因子和组蛋白修饰因子.我们对94个ACC组织的公开RNA-seq数据集进行了详细的生物信息学分析，并补充了临床数据和相应的对照，并生成了染色质和组蛋白修饰因子的蛋白质-蛋白质相互作用（PPI）网络。TP53和组蛋白修饰酶SUV39H1，EZH2，PRMT1，HDAC8和KDM5B的显着上调，随着DNA甲基转移酶DNMT3A和泛素连接酶UHRF1mRNA水平的上调，以及赖氨酸乙酰转移酶KAT2B水平的下调，在ACC组织中检测到。在SGT组织中进一步验证了p53，SUV39H1，EZH2和HDAC8的蛋白表达，以及它们分别对抑制组蛋白标记H3K9me3和H3K27me3的功能沉积。总的来说,这项研究是第一个检测到影响唾液腺肿瘤细胞染色质结构和组蛋白修饰的相互作用蛋白网络，进一步提供对SGT分子谱的机械见解，赋予改变的基因表达程序。
