Identification of Oncogenic Potential of SIRT7 and Its Regulatory MicroRNAs in Liver Tumorigenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE33234 | GEO | 2012/03/01
SECONDARY ACCESSION(S): PRJNA149423
REPOSITORIES: GEO
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Project description:To investigate the specific roles of SIRT7 in the development of HCC, we employed large-scale gene expression analysis to identify the molecular signature that may affect enabling characteristics of cancer cells. Differentially expressed genes were analyzed on the Hep3B cells transfected with SIRT7 shRNAs, and recapitulated molecular signatures that related to hallmarks of cancer. For each of the experimental conditions, total RNA was extracted from three independent sets of the corresponding cell lines using TRIzol Reagent (Invitrogen), followed by clean up on Ambion columns (Illumina Total-Prep RNA Amplification Kit, Ambion). For each experimental condition, an RNA pool was then obtained by mixing equal quantities of total RNA from each of the three independent RNA extractions. Biotin-labelled cRNA targets were synthesized starting from 1.5 µg of total RNA. Double stranded cDNA synthesis was performed with Illumina® TotalPrep RNA Amplification Kit (Ambion), and biotin-UTP-labelled antisense RNA was transcribed in vitro using Ambion’s Kit. All steps of the labelling protocol were performed as suggested by Ambion (http://www.ambion.com/techlib/prot/ fm_IL1791.pdf). The size and the accuracy of quantitation of targets were checked by Experion (Bio-rad Laboratories., Hercules, CA) electrophoresis system, prior to and after cRNA purification. After purification, targets were diluted in hybridization buffer at a concentration of 240 ng/µl, and hybridization was allowed to proceed at 58°C for 20 h. For microarray analysis, the Illumina HumanHT-12 v4 Sentrix Expression BeadChip was used (Illumina, San Diego, CA). Hybridization of labelled cRNA to the BeadChip, washing, and scanning were performed according to the Illumina BeadStation 500× manual. The array signal was developed via 10-min incubation with streptavidin-Cy3. The HumanHT-12 v4 Sentrix Expression BeadChip was washed and subsequently dried via centrifugation for 4 min at a setting of 275 xg. The arrays were scanned on the Illumina BeadArray reader, a confocal-type imaging system with 532 (Cy3) nm laser illumination. Data from each sample was extracted with Genome Studio software (Illumina) using default parameters and then analyzed using GenPlex 3.0.
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Project description:SIRT7 is a member of the mammalian sirtuin family of NAD+ dependent deacylases, and interacts with RNA polymerase I and UBF to regulate rDNA transcription. Various studies in mammalian cells and human clinical data have linked SIRT7 to cancer. However studies differ as to whether SIRT7 is oncogenic or tumor suppressive. Here we analyzed SIRT7 knockout mice and found SIRT7 deficiency caused sub-Mendelian birth numbers and a reduction in body size. Moreover, at 18 month of age, roughly 60 % of the SIRT7 knockout mice develop hepatocellular carcinoma (HCC), in many cases leading to suspected metastasis. Several HCC associated genes were up-regulated in livers of mice as young as 6 months of age, particularly targets of the proto-oncogene, c- MYC. Indeed SIRT7 interacts with MYC at endogenous protein levels and also represses MYC activity. Our findings thus show that SIRT7 acts as a tumor suppressor in vivo, and may suggest novel strategies to treat liver cancer. The mRNAs from 3 replicates of mouse Wildtype liver compared to 3 replicates of mouse liver lacking SIRT7
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2012-03-01 | GSE32070 | GEO
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Project description:SIRT7 is a member of the mammalian sirtuin family of NAD+ dependent deacylases, and interacts with RNA polymerase I and UBF to regulate rDNA transcription. Various studies in mammalian cells and human clinical data have linked SIRT7 to cancer. However studies differ as to whether SIRT7 is oncogenic or tumor suppressive. Here we analyzed SIRT7 knockout mice and found SIRT7 deficiency caused sub-Mendelian birth numbers and a reduction in body size. Moreover, at 18 month of age, roughly 60 % of the SIRT7 knockout mice develop hepatocellular carcinoma (HCC), in many cases leading to suspected metastasis. Several HCC associated genes were up-regulated in livers of mice as young as 6 months of age, particularly targets of the proto-oncogene, c- MYC. Indeed SIRT7 interacts with MYC at endogenous protein levels and also represses MYC activity. Our findings thus show that SIRT7 acts as a tumor suppressor in vivo, and may suggest novel strategies to treat liver cancer.
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Project description:SIRT7 is a member of the mammalian sirtuin family and functions as a NAD+-dependent deacylase. Studies in culture cells and human clinical data have implicated the role of SIRT7 in tumorigenesis. However, controversies were raised as to whether SIRT7 is oncogenic or tumor suppressive. Here we show that SIRT7 deficiency led to aneuploidy and aging-phenotypes, including senescence and nucleolin expansion. SIRT7 knockout mice were susceptible to DSS-induced colitis and alcohol-derived DNA damage, in advance led to intestinal epithelial barrier disruption. Devoid of SIRT7 aggravated the susceptibility of colorectal cancer incidence in APCMin/+ mouse model with further dysregulated Wnt signaling. Our findings indicated a tumor suppressive role of SIRT7 in vivo, novel strategies design for activating SIRT7 in treating colon cancer may be reappraised.
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Project description:Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism, and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets, and physiologic functions have been unclear. Here we show that SIRT7 is an NAD+-dependent, histone H3 acetyl-lysine 18 (H3K18Ac) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by interaction of SIRT7 with the cancer-related ETS transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has recently been linked to oncogenic transformation, and in patients, is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells including anchorage independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by viral oncoproteins. Finally, SIRT7 depletion markedly reduces the tumourigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as the first known site-specific H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs, and tumour formation in vivo.
2012-05-07 | GSE28149 | GEO
Project description:To investigate the specific roles of HDAC6 in the development of liver cancer, we employed large-scale gene expression analysis to identify the molecular signature that may affect enabling characteristics of cancer cells. Differentially expressed genes were analyzed on the Hep3B cells transfected with empty mock or pcDNA_HDAC6, and recapitulated molecular signatures that related to hallmarks of cancer. To characterize the biological effects of HDAC6 on liver cancer, large-scale gene expression analysis to identify molecular signature was performed on the Hep3B cells.
2012-03-01 | E-GEOD-32068 | biostudies-arrayexpress
Project description:To investigate the specific roles of HDAC6 in the development of liver cancer, we employed large-scale gene expression analysis to identify the molecular signature that may affect enabling characteristics of cancer cells. Differentially expressed genes were analyzed on the Hep3B cells transfected with empty mock or pcDNA_HDAC6, and recapitulated molecular signatures that related to hallmarks of cancer.
2012-03-01 | GSE32068 | GEO