Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD 1 )-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G 1 /S phase and to suppress growth. This treatment restored p21, induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21 WAF1/Cip1 -dependent G 1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2 0 -deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Conclusion: Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21 WAF1/Cip1 by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2013;57:1055-1067 S irtuins, also designated as class III histone deacetylases, are nicotinamide adenine dinucleotide oxidized form (NAD þ )-dependent deacetylases that target histone and nonhistone proteins and are implicated in the control of a wide range of biological processes such as apoptosis, stress responses, DNA repair, cell cycle, metabolism, and senescence. 1 The importance of sirtuins is demonstrated by their role in several major human pathologic conditions, including cancer, diabetes, cardiovascular disease, and neurodegenerative disease. 2 Mammals express seven sirtuins (denoted SIRT1-7) that have considerably different functions and catalytic activities. 3 The most closely related to yeast Sir2 and the best-characterized sirtuin, Abbreviations: 5-aza-dC, 5-aza-2 0 -deoxycytidine; CDKN1A, cyclin dependent kinase 1A;

Accumulated evidence has established that aberrant regulation of histone deacetylases (HDACs) is one of the major causes of the development of human malignancies. Among different iso-enzymes of HDAC and sirtuins grouped as the HDAC super family, little is known as to how histone deacetylase 2 (HDAC2) causes carcinogenesis in solid tumors. Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry. Moderate to strong expression of HDAC2 was found in 44 (62%) out of a total of 71 tumors. The majority of positive tumors, which were detected in the nucleus but not in normal gastric epithelium, did not express HDAC2 or showed only weak positive staining. Interestingly, we also noted that HDAC2 expression appeared to be associated with tumor aggressiveness as HDAC2 expression was observed to be statistically significant in advanced gastric cancer (P=0.0023, Chi-square test) and in positive lymph node metastasis (P=0.0713, Chi-square test). Taken together, these results suggest that HDAC2 may play an important role in the aggressiveness of gastric cancer.

The findings suggest molecular markers of BANF1, PLOD3, and SF3B4 indicating early-stage HCC in precancerous lesion, and also suggest drivers for understanding the development of hepatocarcinogenesis. (Hepatology 2018;67:1360-1377).

Ubiquitin-binding histone deacetylase 6 (HDAC6) is uniquely endowed with tubulin deacetylase activity and plays an important role in the clearance of misfolded protein by autophagy. In cancer, HDAC6 has become a target for drug development due to its major contribution to oncogenic cell transformation. In the present study we show that HDAC6 expression was down-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients, and that low expression of HDAC6 was significantly associated with poor prognosis of HCC patients in 5-year overall, disease-free, and recurrence-free survival. Notably, we observed that ectopic overexpression of HDAC6 suppressed tumor cell growth and proliferation in various liver cancer cells, and elicited increased LC3B-II conversion and autophagic vacuole formation without causing apoptotic cell death or cell cycle inhibition. In addition, the sustained overexpression of HDAC6 reduced the in vivo tumor growth rate in a mouse xenograft model. It was also found that HDAC6 mediated autophagic cell death by way of Beclin 1 and activation of the LC3-II pathway in liver cancer cells, and that HDAC6 overexpression activated c-Jun NH2-terminal kinase (JNK) and increased the phosphorylation of c-Jun. In contrast, the induction of Beclin 1 expression was blocked by SP600125 (a specific inhibitor of JNK) or by small interfering RNA directed against HDAC6. Conclusion: Our findings suggest that loss of HDAC6 expression in human HCCs and tumor suppression by HDAC6 occur by way of activation of caspase-independent autophagic cell death through the JNK/Beclin 1 pathway in liver cancer and, thus, that a novel tumor suppressor function mechanism involving HDAC6 may be amenable to nonepigenetic regulation. (HEPATOLOGY 2012;56:644-657) H epatocellular carcinoma (HCC) is an aggressive form of cancer, the fifth most common cancer, and the third leading cause of cancer death worldwide. 1 Surgery with curative intent is feasible for only 15% to 25% of patients and most HCC patients die from locally advanced or metastatic disease in a relatively short period of time. 2 Hepatitis B virus, hepatitis C virus, and aflatoxin B1 are well-known major causes of HCC. However, the overall survival of patients with HCC has not improved significantly over the past two decades, and the mechanisms responsible for the development and progression of HCC remain poorly understood. 3 To date, molecular targeted therapy has shown promise for the treatment of advanced Abbreviations: 3-MA, 3-methyladenine; FACS, fluorescence-activated cell sorting; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HAT, histone acetyltransferase; HCC, hepatocellular carcinoma; HDAC, histone deacetylases; JNK, c-Jun NH2-terminal kinase; LC3, microtubule-associated protein 1 light chain 3; mRNA, messenger RNA; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly (ADP-ribose) polymerase; siRNA, small interfering RNA; TEM, transmission electron microscopy; TMA, tissue microarray.From the