Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism.

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.

The Role of Bone Morphogenetic Protein 9 in Nonalcoholic Fatty Liver Disease in Mice.

Background and Aims: It's reported that bone morphogenetic protein 9 (BMP9) played an important role in lipid and glucose metabolism, but the role of BMP9 in nonalcoholic fatty liver disease (NAFLD) is unclear. Here, we evaluated the therapeutic efficacy of recombined BMP9 in NAFLD mice and investigated the potential mechanism. Methods: The effects of recombinant BMP9 on NAFLD were assessed in HFD-induced NAFLD mice. C57BL/6 mice were administrated with high-fat diet (HFD) for 12 weeks. In the last 4 weeks, mice were treated with PBS or recombined BMP9 once daily. Insulin sensitivity was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT) at the end of the 12th week. Then NAFLD related indicators were assessed by a variety of biological methods, including histology, western blotting, real-time PCR, RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses. Results: BMP9 reduced obesity, improved glucose metabolism, alleviated hepatic steatosis and decreased liver macrophages infiltration in HFD mice. RNA-seq showed that Cers6, Cidea, Fabp4 involved in lipid and glucose metabolism and Fos, Ccl2, Tlr1 involved in inflammatory response downregulated significantly after BMP9 treatment in HFD mouse liver. ATAC-seq showed that chromatin accessibility on promoters of Cers6, Fabp4, Ccl2 and Fos decreased after BMP9 treatment in HFD mouse liver. KEGG pathway analysis of dysregulated genes in RNA-seq and integration of RNA-seq and ATAC-seq showed that TNF signaling pathway and Toll-like receptor signaling pathway decreased in BMP9 treated HFD mouse liver. Conclusion: Our data revealed that BMP9 might alleviate NAFLD via improving glucose and lipid metabolism, decreasing inflammatory response and reshaping chromatin accessibility in HFD mouse liver. BMP9 downregulate genes related to lipid metabolism, glucose metabolism and inflammation expression, at least partially via decreasing promoter chromatin accessibility of Cers6, Fabp4, Fos and Tlr1. BMP9 may also reduce the expression of liver Ccl2, thereby changing the number or composition of liver macrophages, and ultimately reducing liver inflammation. The effect of BMP9 on NAFLD might be all-round, and not limit to lipid and glucose metabolism. Therefore, the underlying mechanism needs to be studied in detail further.

Resistance of Helicobacter pylori to antibiotics from 2000 to 2009 in Shanghai.

AIM: To investigate the resistance of Helicobacter pylori (H. pylori) to 6 commonly used antibiotics from 2000 to 2009 in Shanghai. METHODS: A total of 293 H. pylori strains were collected from 2000 to 2009 in Shanghai and tested for their susceptibility to metronidazole, clarithromycin, amoxicillin, furazolidone, levofloxacin and tetracycline using agar dilution. RESULTS: The resistant rates of H. pylori to clarithromycin (8.6%, 9.0% and 20.7%) and levofloxacin (10.3%, 24.0% and 32.5%) increased from 2000 to 2009 in Shanghai. The resistant rate of H. pylori to metronidazole remained stable (40%-50%). Only one strain of H. pylori isolated in 2005 was resistant to tetracycline. All strains were sensitive to amoxicillin and furazolidone. The resistant rate of H. pylori to antibiotics was not related with the sex, age and clinical outcome of patients. CONCLUSION: Resistance of H. pylori to antibiotics plays an important role in making treatment strategies against H. pylori-associated diseases.

Comparison of the efficacy of triple versus quadruple therapy on the eradication of Helicobacter pylori and antibiotic resistance.

OBJECTIVE: Our aim was to compare the efficacy and safety of Helicobacter pylori (H. pylori) eradication with pantoprazole-based 7-day standard triple therapy (PAC) and 10-day quadruple therapy (PBMT), and to study the primary resistance of H. pylori to amoxicillin, clarithromycin, metronidazole and tetracycline. METHODS: A total of 170 patients with non-ulcer dyspepsia (NUD) and H. pylori infection were allocated to two study groups. The PAC group received pantoprazole 40 mg b.i.d., amoxicillin 1.0 g b.i.d. and clarithromycin 500 mg b.i.d. for 7 days; the PBMT group received pantoprazole 40 mg b.i.d., colloidal bismuth subcitrate 220 mg b.i.d, metronidazole 400 mg t.i.d. and tetracycline 750 mg b.i.d. for 10 days. A total of 80 H. pylori strains were isolated and antibiotic resistance was measured by the agar dilution method. RESULTS: A total of 166 patients completed the therapy. The intention-to-treat eradication rates in the PAC and PBMT groups were 63.5% and 89.4%, respectively (P < 0.05). By per protocol analysis, the eradication rates of the two groups were 65.1% and 91.6%, respectively (P < 0.05). Overall 77 clinical isolated H. pylori strains were cultured successfully. The H. pylori primary resistance rates to metronidazole and clarithromycin were 41.6% and 20.8%, respectively, whereas all the H. pylori isolates were sensitive to amoxicillin and tetracycline. CONCLUSION: The efficacy of PAC declines in many regions in China because of high antibiotic resistance rates. The PBMT regimen achieved a high eradication rate of H. pylori and might be used as a first-line therapy.