SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

• Published in: Nature (London) 2012-07, Vol.487 (7405), p.114-118
• Main Authors: Barber, Matthew F., Michishita-Kioi, Eriko, Xi, Yuanxin, Tasselli, Luisa, Kioi, Mitomu, Moqtaderi, Zarmik, Tennen, Ruth I., Paredes, Silvana, Young, Nicolas L., Chen, Kaifu, Struhl, Kevin, Garcia, Benjamin A., Gozani, Or, Li, Wei, Chua, Katrin F.
• Format: Article
• Language: English
• Subjects: 631/67/395; 631/67/69; Acetylation; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Animals; Base Sequence; Binding Sites; Biological and medical sciences; Cancer; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chromatin - metabolism; Contact Inhibition; Disease Progression; Epigenetics; ets-Domain Protein Elk-4 - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic transformation; Genetics; Histone Deacetylases - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; letter; Lysine - metabolism; Mass spectrometry; Mice; Molecular and cellular biology; multidisciplinary; Neoplasm Transplantation; Nucleotide Motifs; Oncogenes; Phenotype; Promoter Regions, Genetic; Properties; Proteins; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Sirtuins - deficiency; Sirtuins - genetics; Sirtuins - metabolism; Transcription, Genetic; Transplantation, Heterologous
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11043

SIRT7 is an H3K18Ac-selective deacetylase that has a pivotal role in chromatin regulation, maintenance of cellular transformation programs and tumour formation in vivo . Sirtuin 7 involved in tumour progression The mammalian sirtuin protein SIRT7 has been linked to the transcription of ribosomal RNA but, unlike other known human sirtuins, its substrates and physiological function are not clear. This paper reports an enzyme activity for SIRT7 and provides several strands of evidence linking SIRT7 activity to the maintenance of fundamental cancer-cell phenotypes and tumour progression. SIRT7 acts as a histone deacetylase specific for H3 lysine 18, and promotes transcriptional repression. SIRT7 target genes have links to tumour suppression, and the oncogenic transcription factor ELK4 can recruit SIRT7 to target promoters. SIRT7 is required for the maintenance of cellular transformation and tumour growth in mice. Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing 1 , 2 . SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD + -dependent H3K18Ac (acetylated lysine 18 of histone H3) 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 its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis 3 , 4 , 5 , 6 . 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 the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transform