SIRT7 Antagonizes TGF-β Signaling and Inhibits Breast Cancer Metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99596 | GEO | 2017/06/03
SECONDARY ACCESSION(S): PRJNA388881
REPOSITORIES: GEO
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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. SIRT7 ChIP-seq was performed in K562 cell lines under normal conditions. Two replicates were performed for both the SIRT7 ChIP as well as input control.
2012-05-06 | E-GEOD-28149 | biostudies-arrayexpress
Project description: Not available
| S-EPMC5566498 | biostudies-literature
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:SIRT7 is an NAD+-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-rRNA and promotes rRNA synthesis. Here we show that SIRT7 is also associated with snoRNAs that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA-dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of prerRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA. CLIP-seq was performed in Flag-SIRT7-293T cells.
2016-01-07 | E-GEOD-76578 | biostudies-arrayexpress
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
2014-08-20 | E-GEOD-50076 | biostudies-arrayexpress
Project description:We report that RNA can increase the catalytic efficiency of SIRT7 and that SIRT7 can remove long chain fatty acyl groups more efficiently than removing acetyl groups. Truncation and mutagenesis studies revealed residues at both the amino and carboxyl termini of SIRT7 that are involved in RNA-binding and important for activity. RNA immunoprecipitation-sequencing (RIP-seq) identified ribosomal RNA (rRNA) as the predominant RNA binding partners of SIRT7. The associated RNA was able to effectively activate the deacetylase and defatty-acylase activities of SIRT7. These findings provide important insights into the biological functions of SIRT7, as well as an improved platform to develop SIRT7 modulators.
2017-02-17 | GSE81839 | GEO
Project description:We report that RNA can increase the catalytic efficiency of SIRT7 and that SIRT7 can remove long chain fatty acyl groups more efficiently than removing acetyl groups. Truncation and mutagenesis studies revealed residues at both the amino and carboxyl termini of SIRT7 that are involved in RNA-binding and important for activity. RNA immunoprecipitation-sequencing (RIP-seq) identified ribosomal RNA (rRNA) as the predominant RNA binding partners of SIRT7. The associated RNA was able to effectively activate the deacetylase and defatty-acylase activities of SIRT7. These findings provide important insights into the biological functions of SIRT7, as well as an improved platform to develop SIRT7 modulators.
2017-02-17 | GSE81840 | GEO
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.
2020-09-16 | GSE138289 | GEO
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.
2014-08-20 | GSE50076 | GEO
Project description:SIRT7 is an NAD+-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-rRNA and promotes rRNA synthesis. Here we show that SIRT7 is also associated with snoRNAs that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA-dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of prerRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA.
2016-01-07 | GSE76578 | GEO