SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

Abstract

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism, and ageing1,2. 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 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 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 prognosis3–6. 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 tumourigenicity 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.

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

“…Further hits, such as phosphatidylinositol-4-phosphate 5-kinase (Lys145), indicate Sirt6 connections to other signalling pathways. For Sirt7, we identified in p53, its only known substrate protein besides histone H3 11,12 , Lys382 as a strongly deacetylated site (also a Sirt1 substrate site 6 ). Novel potential substrates include transcription factors (for example, Myocytespecific enhancer factor 2C, MEF-2C; Lys239) and DNA-dependent protein kinase (Lys117), indicating that Sirt7 regulates DNA structure and function.…”

“…Sirt6 regulates DNA stability and repair 7 , and histone H3 and 'C-terminal-binding protein-interacting protein' were identified as first deacetylation substrates 8,9 . Sirt7 regulates RNA polymerase I 10 and can deacetylate p53 and histone H3 11,12 . Sirt3, 4 and 5 are located in mitochondria 13 .…”

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…SIRT7 is detected at promoters and coding regions of ribosomal genes, where it positively controls ribosome production through direct interaction with the PolI machinery (Ford et al , 2006; Grob et al , 2009; Chen et al , 2013). Conversely, SIRT7 negatively regulates the transcription of genes outside of the rDNA repeats via histone H3K18 deacetylation (Barber et al , 2012). Recent evidence indicates that SIRT7 may have the capacity to act as an oncogene as its expression is elevated in several human cancers (Roth & Chen, 2014).…”

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…In contrast, Sirt7 did not affect expression of satellite repeats despite the fact that Sirt7 is able to specifically deacetylate H3K18 [4,5]. The lack of Sirt7 influence on satellite repeats transcription is puzzling in view of the higher Suv39h1 recruitment to the pericentric heterochromatin demonstrated in our paper and requires further investigation.…”