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Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are diseases of abnormal hematopoietic differentiation with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA methyltransferase inhibitor widely used to treat MDS and AML, yet the impact of AZA on the cell-surface proteome has not been defined. To identify potential therapeutic targets for use in combination with AZA in AML patients, we investigated the effects of AZA treatment on four AML cell lines representing different stages of differentiation. The effect of AZA treatment on these cell lines was characterized at three levels: the DNA methylome, the transcriptome, and the cell-surface proteome. Untreated AML cell lines showed substantial overlap at all three omics levels; however, while AZA treatment globally reduced DNA methylation in all cell lines, changes in the transcriptome and surface proteome were subtle and differed among the cell lines. Transcriptome analysis identified five commonly up-regulated coding genes upon AZA treatment in all four cell lines, TRPM4 being the only gene encoding a surface protein, and surface proteome analysis found no commonly regulated proteins. Gene set enrichment analysis of differentially regulated RNA and surface proteins showed a decrease in metabolic pathways and an increase in immune defense response pathways. As such, AZA treatment led to diverse effects at the individual gene and protein levels but converged to common responses at the pathway level. Given the heterogeneous responses in the four cell lines, we discuss potential therapeutic strategies for AML in combination with AZA.

T‐cell exhaustion is one of the hallmarks in cancer, but the mechanisms underlying T‐cell dysregulation remains unclear. Here, we reported that down‐regulation of transcription factor EOMES contributed to increased levels of inhibitory receptors in T cell among the tumour tissues and resulted in the poor prognosis of hepatocellular carcinoma (HCC). By analysing the correlation between EOMES in tumour‐infiltrating T cells and the clinical features, we demonstrated that the EOMES was related to the advanced stage and poor prognosis of HCC. Further mechanistic studies revealed that the EOMES mainly expressed in the CD8+ T cells and were down‐regulated in tumour samples. Moreover, we demonstrated that the EOMES directly bound at the transcriptional regulatory regions of the key inhibitory factors including PD‐1, CTAL‐4 and CD39, and lower levels of EOMES contributed to overexpression of these factors in T cells. Together, our studies provide new insight into the transcriptional deregulation of the inhibitory receptors on T cells during the tumorigenesis. [ABSTRACT FROM AUTHOR]

Comparative ChIP-seq data reveal adaptive evolution of insulator protein CTCF binding in multiple Drosophila species. [ABSTRACT FROM AUTHOR]

Chemoresistance in gastric cancer is the leading cause of tumor recurrence and poses a substantial therapeutic challenge. The stem cell biomarker CD133 has been implicated in drug resistance of tumor-initiating cells in a number of cancers including gastric cancer. Therefore, we investigated the molecular mechanism of CD133-associated multidrug resistance in gastric cancer cells. Using CD133 overexpressing and knockdown gastric cancer cell lines, we demonstrated that loss of CD133 significantly increased the growth inhibition of chemotherapeutic agents; whereas, overexpression significantly reduced growth inhibition. Furthermore, CD133 knockdown significantly reduced the enzymatic activity of phosphatidylinositol-3 kinase (PI3K) and the expression of P-glycoprotein (P-gp), B-cell lymphoma 2 (BCL2), and phosphorylated-protein kinase B (p-AKT), but elevated the expression of BCL2 associated X (BAX). Conversely, overexpression of CD133 significantly increased PI3K enzymatic activity, expression of P-gp, BCL2, and p-AKT, and decreased BAX expression. The PI3K/AKT inhibitor LY294002 mirrored the effects of loss of CD133; whereas, the PI3K/AKT activator epidermal growth factor reproduced the effects of CD133 overexpression. To identify the interaction between CD133 and PI3K, we used site-directed mutagenesis to mutate individual tyrosine residues of CD133. We found that binding between CD133 and p85, the regulatory subunit of PI3K, was significantly reduced when tyrosine 852 was mutated. In summary, we have demonstrated that CD133 activates the PI3K/AKT signal transduction pathway through direct interaction with PI3K-p85, resulting in multidrug resistance of gastric cancer cells. These results suggest that the interaction between CD133 and PI3K-p85 may offer a novel therapeutic target in multidrug resistant gastric cancer., Competing Interests: None.