Background:Epigenetic therapy using histone deacetylase inhibitors (HDACi) has shown promise in clinical trials for the treatment of human malignancies. In addition to the immediate effects on the tumour cell growth, HDACi upregulates the expression of MHC class I-related chain molecules A and B (MICA and MICB), resulting in an enhanced susceptibility of tumour cells to natural killer cell-mediated lysis. The molecular mechanism underlying is still unclear.Methods:The transcriptional regulation mechanism underlying suberoylanilide hydroxamic acid (SAHA)-mediated regulation of MICA and related miRNA expression was investigated using promoter acetylation assays, bioinformatics analysis and chromatin immunoprecipitation assay.Results:SAHA upregulates the transcription of MICA/B by promoting MICA-associated histone acetylation while suppressing the MICA/B-targeting miRNAs miR-20a, miR-93 and miR-106b. The mechanism by which SAHA repressed miRNAs transcription involved repression of their host genes (miR-17-92 cluster and MCM7). SAHA downregulated the miR-17-92 cluster by abolishing tyrosine phosphorylation of STAT3 and decreased MCM7 transcription through localised histone deacetylation.Conclusions:The HDACi SAHA epigenetically upregulates MICA expression through regulating the expression of miR-17-92 cluster and MCM7 in hepatoma, thus enhancing the sensitivity of HCC to natural killer cell-mediated lysis. This novel mechanism of action provides promise for HDACi in therapy of HCC.

DNA methylation and histone modifications have emerged as key mechanisms in transcriptional regulation. The target of methylation-induced silencing 1 (TMS1) is a bipartite protein. Recent studies have indicated that methylation-associated silencing of TMS1 occurs in many cancers. However, whether and how TMS1 is regulated by epigenetic mechanisms in cancers remains unknown. In this study we showed that methylation of the TMS1 promoter occurred in five of six hepatocellular carcinoma (HCC) cell lines. TMS1 expression was reduced in four HCC cell lines and correlated with methylation status. Furthermore, the TMS1 promoter was completely methylated and mRNA expression was undetectable. TMS1 expression could be restored by 5-aza-2'-deoxycitidine (5-Aza-dC) (a DNA methyltransferase inhibitor) or trichostatin A (TSA) (a histone deacetylase inhibitor) alone and the promoter methylation was partially reversible. TSA was more efficient than 5-Aza-dC in inducing TMS1 expression, and the combination of 5-Aza-dC and TSA resulted in markedly synergistic reactivation of the gene and completely reversed promoter methylation. Interestingly, TMS1 promoter methylation-associated gene silencing was accompanied by histone H3 Lysine 9 (H3K9) hypoacetylation and trimethylation. 5-Aza-dC and/or TSA also had some effect on conversion of methylated to acetylated H3K9 in restoring TMS1. This conversion was dynamic at the TMS1 promoter and a decrease in H3K9 trimethylation preceded an increase in H3K9 acetylation after 5-Aza-dC and/or TSA treatment. Our results thus suggest that epigenetic inactivation of TMS1 expression is regulated by promoter hypermethylation and H3K9 modifications in a coordinated way.

ABSTRACT. We compared serum levels of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, matrix metalloproteinase (MMP)-1, and MMP-3 in patients with different stages of knee osteoarthritis (OA), and investigated the clinical significance of diagnosing OA in early stages. OA patients were divided into 2 groups: early OA group (44 cases), intermediate and advanced OA group (26 cases). The healthy control group included 30 samples. ADAMTS-4, ADAMTS-5, MMP-1, and MMP-3 levels in the serum were tested using an enzyme-linked immunosorbent assay. A protein-protein interaction network was constructed by seeding the significantly expressed marker, followed by Gene Ontology enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. ADAMTS-4 levels were significantly higher in patients at early stages of OA compared to intermediate or advanced OA and healthy controls. ADAMTS-5, MMP-1, and MMP-3 levels in intermediate and advanced-stage OA patients were significantly higher than those in early-stage OA patients and healthy controls. The proteinprotein interaction network showed that ADAMTS-4 participates in

Trends in incidence and prevalence of hypertension are grave in China and identifying high-risk, non-hypertension individuals for intervention may delay hypertension onset. We aimed to investigate the incidence of hypertension in northern urban Han Chinese population and construct multivariable hypertension prediction models through the prospective cohort, which included 7537 men and 4960 women free of hypertension at baseline between 2005 and 2010. During 38 958 person-years of follow-up, 2785 participants (men, 72.57%; women, 27.43%) developed hypertension. The incidence density of hypertension was 71.48 per 1000 person-year. In multivariable backward cox analyses, age, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose and current drinking were retained for both men and women, while gamma-glutamyl transferase only for men, total cholesterol, neutrophil granulocyte and current smoking only for women. The area under receiver operating characteristic curve (AUC) was 0.761 (95% confidence interval (CI), 0.752-0.771) for men and 0.753 (95% CI, 0.741-0.765) for women, even after 10-fold cross-validation, the AUC was 0.760 (95% CI, 0.751-0.770) for men and 0.749 (95% CI, 0.737-0.761) for women. Through risk stratification, the absolute risk of incident hypertension in 5 years at moderate, high and very high risk level was 2.13, 3.84 and 6.14 times that of those who were at low risk in men, and 1.30, 2.56 and 6.01 times that of those who were at low risk in women. Our findings identified predictors of incident hypertension and indicated that the sex-specific multivariable prediction models would be simply used to estimate the risk of incident hypertension.