Salivary gland tumors (SGTs) comprise a rare and heterogenous category of benign/malignant neoplasms with progressively increasing knowledge of the molecular mechanisms underpinning their pathogenesis, poor prognosis, and therapeutic treatment efficacy. Emerging data are pointing toward an interplay of genetic and epigenetic factors contributing to their heterogeneity and diverse clinical phenotypes. Post-translational histone modifications such as histone acetylation/deacetylation have been shown to actively participate in the pathobiology of SGTs, further suggesting that histone deacetylating factors (HDACs), selective or pan-HDAC inhibitors (HDACis), might present effective treatment options for these neoplasms. Herein, we describe the molecular and epigenetic mechanisms underlying the pathology of the different types of SGTs, focusing on histone acetylation/deacetylation effects on gene expression as well as the progress of HDACis in SGT therapy and the current status of relevant clinical trials.

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.

Acute Myeloid Leukemia (AML) is a life-threatening disease whose induction treatment consists of combination chemotherapy with Idarubicin and Cytarabine for fit patients. Treatment failures are frequent, urging the need for novel treatments for this disease. The DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis. AML-derived cell lines after treatment with Idarubicin and Cytarabine were used for studying the expression profile of 84 DDR genes, through PCR arrays. Utilizing de novo AML patient and control samples we studied the expression of PPP1R15A, CDKN1A, GADD45A, GADD45G, and EXO1. Next, we performed PPP1R15A silencing in AML cell lines in two separate experiments using siRNA and CRISPR-cas9, respectively. Our findings highlight that DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients. The PPP1R15A silencing resulted in decreased viability of Idarubicin and Cytarabine-treated cell lines, in contrast to untreated cells. These findings shed light on new strategies to enhance chemotherapy efficacy and demonstrate that PPP1R15A is an important DDR regulator in AML and its downregulation might be a safe and effective way to increase sensitivity to chemotherapy in this disease.

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C₂H₂-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

Acute Myeloid Leukemia (AML) is a life-threatening disease whose induction treatment consists of combination chemotherapy with Idarubicin and Cytarabine for fit patients. Treatment failures are frequent, urging the need for novel treatments for this disease. The DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis. AML-derived cell lines after treatment with Idarubicin and Cytarabine were used for studying the expression profile of 84 DDR genes, through PCR arrays. Utilizing de novo AML patient and control samples we studied the expression of PPP1R15A, CDKN1A, GADD45A, GADD45G, and EXO1. Next, we performed PPP1R15A silencing in AML cell lines in two separate experiments using siRNA and CRISPR-cas9, respectively. Our findings highlight that DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients. The PPP1R15A silencing resulted in decreased viability of Idarubicin and Cytarabine-treated cell lines, in contrast to untreated cells. These findings shed light on new strategies to enhance chemotherapy efficacy and demonstrate that PPP1R15A is an important DDR regulator in AML and its downregulation might be a safe and effective way to increase sensitivity to chemotherapy in this disease.

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted.