Sirtuin proteins regulate diverse cellular pathways that influence genomic 
stability, metabolism and ageing. 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. 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 
transformation programs and tumour formation in vivo.