To study the relationship between clock genes and Major Depressive Disorder (MDD).
GEO database was used to obtain the chip data and clinical information of datasets GSE98793, GSE39653 and GSE52790. The differentially expressed clock genes were found through the analysis of the differentially expressed genes between MDD and healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) enrichment analysis were performed on the differential expressed clock genes. Lasso Regression and Support Vector Machine (SVM) method were used for screening the differential expressed clock genes. Logistic regression was used to establish a diagnostic model for depression with the screened genes. Receiver Operating Characteristic (ROC) Curve was used to verify the model. Gene differential expression analysis was performed for MDD with high scores and MDD with low scores in the diagnostic model. Gene Set Enrichment Analysis (GSEA) enrichment analysis was performed for differentially expressed genes. Single-gene GSEA was used to analyze each gene in the model separately. Cibersort method was used to analyze the immune infiltration of MDD and healthy controls, and the correlation between immune cells and clock genes was analyzed. Cytoscape was used to analyze the clock gene interaction network. The DGIdb website was used to predict potentially effective therapeutic drugs for clock genes closely related to MDD.
Six genes were identified by differential expression analysis of clock genes between MDD and healthy controls. GO and KEGG enrichment analysis of 6 genes showed that their pathways were concentrated such as circadian rhythm, rhythmic process, TGF - beta signaling pathway, longevity regulating pathway-multiple species, adipocytokine signaling pathway and so on. Lasso regression and SVM were used to screen out 5 clock genes (HDAC1, ID3, NFIL3, PRKAA1, TNF) for MDD. The diagnostic model of depression was established according to the 5 clock genes. The area under the curve (AUC) of the established depression diagnostic model was 0.686. Gene difference analysis was performed between MDD patients with high score of clock gene diagnostic model and MDD patients with low score. GSEA was performed for the differential genes showed that the most enriched pathways were:adipocytokine signaling pathway, TGF beta signaling pathway, oxidative phosphorylation, primary immunodeficiency, and so on. The single gene GSEA showed that the most enriched pathways were Toll like receptor signaling pathway, glucolipid metabolism, amino acid metabolism, neuroactive ligand receptor interaction, and so on. The results of immune infiltration analysis showed that NK cells resting and Macrophages M2 were different between MDD and control groups. In MDD, the gene closely related to NK cells resting was HDAC1, and the genes closely related to Macrophages M2 were HDAC1 and NFIL3. The RNA interactions network of clock genes shows that the regulation process is complex, which can provide a reference for subsequent related research. Potential therapeutic drugs predict display, among the 5 clock genes, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.
Among all CLOCK genes, HDAC1, ID3, NFIL3, PRKAA1, TNF are closely related to MDD. Among them, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.

Histone deacetylases (HDACs) are a group of enzymes that control the expression of genes by deacetylating lysine residues on histone and nonhistone proteins. They control the expression of several proteins linked to the development and spread of cancer. Deregulation of HDAC1 has been reported across several tumors, and targeting HDAC1 with specific inhibitors has demonstrated a promising therapeutic strategy. Mocetinostat, an HDAC1 inhibitor, is yielding promising results both in vitro and in vivo studies. However, toxicities associated with Mocetinostat limit its therapeutic efficacy, so there is an urgent need to investigate novel HDAC1 inhibitors. The present study aimed to explore novel HDAC1 inhibitors and investigate the expression profile, and the prognostic and diagnostic significance of HDAC1 across pan-cancers. HDAC1 was found overexpressed across several tumors and its high expression signifies worse OS and RFS. Also, the study identified two novel HDAC1 inhibitors using an in-silico approach with high binding affinity for HDAC1 compared to Mocetinostat and formed significantly stable complexes. In conclusion, the study signifies that targeting HDAC1 is a promising therapeutic strategy, and exploring novel therapeutic agents through basic, translational design may lead to their ultimate use in cancer prevention.

BACKGROUND: Cancer stem cells (CSCs) are the root of human cancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study.
RESULTS: Overexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer.
CONCLUSIONS: The results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1 is a potential drug target for eradicating SOX4-driven human CSCs.

Histone deacetylases (HDACs) are epigenetic modulators linked to diseases including cancer and neurodegeneration. Given their therapeutic potential, highly sensitive biochemical and cell-based profiling technologies have been developed to discover small-molecule HDAC inhibitors. Ultimately, the therapeutic action of these inhibitors is dependent on a physical engagement with their intended targets in cellular and tissue environments. Confirming target engagement in the cellular environment is particularly relevant for HDACs since they function as part of cell type-specific multiprotein complexes. Here we implemented two recently developed high-throughput target engagement technologies, NanoBRET and SplitLuc CETSA, to profile 349 compounds in the Epigenetic-Focused collection for HDAC1 binding. We found that the two HDAC1 target engagement assays correlated well with each other and with orthogonal activity-based assays, in particular those carried out in cellular environments rather than with isolated HDAC proteins. The assays detected a majority of the previously described HDAC1 inhibitors in the collection and, importantly, triaged HDAC inhibitors known to target other HDACs.

The purpose of this study was to investigate the effects of different concentrations of ethanol on learning and memory in female mice and the corresponding interaction with histone deacetylase 1(HDAC1), estrogen receptor α(ERα) and p21 WAF1/CIP1. Data from the Morris water maze test showed that mice in the 50% ethanol group might experience cognitive impairment, while mice in the 2% ethanol group might experience enhanced cognitive capabilities. The number of damaged neurons in the hippocampal CA1 area in the 50% ethanol group was higher than the numbers observed in other groups. The expression of HDAC1 and ERα proteins was lower in the 50% ethanol group than they were in the control group, while p21 WAF1/CIP1 expression was increased. The expression of these proteins in the 2% ethanol group was completely reversed when compared to the 50% ethanol group. p21 WAF1/CIP1 was involved in the cognitive change induced by ethanol. The f2 (-400 bp to -800 bp) and f7 (-2400 bp to -2800 bp) fragments in the p21 WAF1/CIP1 promoter region were functionally active regions that experienced binding relating to HDAC1 and ERα.