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    • muscarinic receptor antagonists We also conducted analyses o

    2021-11-26

    We also conducted analyses on the functional category of UP_Keywords and on KEGG pathways for further understanding. The UP_Keywords analysis (D) demonstrated that acetylation and phosphoprotein were highly enriched categories. KEGG pathways categories (E) of ribosome biogenesis in eukaryotes, DNA replication, and mismatch repair, were significantly enriched in response to treatment. The significant enrichment in the ribosome biogenesis pathway appears to be consistent with the proteomics analysis of SAHA []. Differential proteins involved in each category are summarized in Table S3 (Supporting information). The protein-protein interaction maps (Fig. S2 in Supporting information) of differential proteins were generated after importing them into the STRING tool and these results are consistent with the biological function enrichment analysis by DAVID enrichment platform. The biological functional analysis helped us to elucidate the effects on biological functions of differential proteins in response to multi-target epigenetic inhibitors. The G1 phase of the muscarinic receptor antagonists is the specific period in which cells make decisions about growth and division. Cyclins and cyclin-dependent kinases (CDKs), which are modulated by a complex mechanism, are the key controlling factors of cell cycle. We found that proteins within the UP_Keywords category of phosphoprotein, which play an important role in cell cycle control from G1 to S phase, were highly enriched. Among these proteins, we observed that compound substantially reduced the expression of several proteins associated with G1 phase cell cycle arrest and apoptosis, including p85, MEK, and CDK4. Interestingly, p85 can modulate phosphorylation of MEK through RAC1/PAK pathway []. We also noted the effect of on the expression of these proteins by immunoblotting. As shown in A, combined inhibition of HDAC and DNMT by can significantly decrease the expression of CDK4 and its modulators, p85 and MEK, and reduce MEK phosphorylation. Taken together, our data demonstrated that induces cell cycle arrest at G1 phase to inhibit cancer progression through upregulating CDK inhibitor p16 and downregulating cyclin-dependent kinases and their activators (B). These results suggest a new potential strategy of HDAC and DNMT inhibitors in cancer therapy. In this study, we reported the dual target epigenetic inhibitor, , which displays potent DNMT1 and HDAC inhibitory activity and exhibits substantial antiproliferative activity against U937 histiocytic lymphoma cells. Our study combined label-free quantitative proteomics with biochemical assays and bioinformatic analysis to investigate the proteome pattern in treated U937 cells. The results indicate that compound , which alters epigenetic modification, could subsequently affect the entire proteome profile and may regulate the expression of key proteins in U937 cells, influencing multiple pathways to induce cell cycle arrest and apoptosis. These results advance the understanding of the underlying pharmacological mechanisms of HDAC and DNMT inhibitors. Acknowledgments We appreciate the financial supports from Shenzhen Development and Reform Committee (No. 20151961), China Postdoctoral Science Foundation (No. 2018M631825) and Department of Science and Technology of Guangdong Province (No. 2017B030314083).
    Development of HDACi HDACs (see Glossary) are epigenetic modulators that remove acetyl groups from histone and nonhistone proteins, and have an important role in the regulation of gene expression. In general, increased acetylation is associated with transcriptional induction, while decreased acetylation is associated with transcriptional repression. Based on their function and sequence homology, HDACs are grouped into four classes, class I–IV (Box 1). Increased expression of HDACs, particularly of class I HDACs, has been associated with a variety of cancers, including hematological malignancies and solid cancers, and correlates with poor prognosis and the development of chemoresistance [1].