Enhanced Transcriptional Signature and Expression of Histone-Modifying Enzymes in Salivary Gland Tumors
Author:
Manou Maria1, Loupis Theodoros2, Vrachnos Dimitrios M.2, Katsoulas Nikolaos3, Theocharis Stamatios3, Kanakoglou Dimitrios S.1ORCID, Basdra Efthimia K.1, Piperi Christina1ORCID, Papavassiliou Athanasios G.1ORCID
Affiliation:
1. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece 2. Haematology Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece 3. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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.
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