SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation

By Matthew F. Barber, Eriko Michishita-Kioi, Yuanxin Xi, L. Tasselli, M. Kioi, Z. Moqtaderi, Ruth I. Tennen, Silvana Paredes, N. L. Young, Kaifu Chen and 4 more. Nature, 2012

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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.

Subfields: Epidemiology, Geriatrics and Gerontology, Oncology

View Paper: https://www.semanticscholar.org/paper/8192c0537e220f9607ef55ed49071cc247e132e0

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Citations in the corpus

Histone Modifications and Cancer. (2016, background): “Hypoacetylation of H3K18, which is indicative of high SIRT7 activity, causes tumor-suppressor gene repression, and is associated with cancer progression and poor prognosis (Seligson et al. 2005; Barber et al. 2012; Paredes et al. 2014).”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “SIRT7 is able to selectively deacetylate the H3K18Ac, which represses the expression of a specific set of gene targets that is linked to oncogenic transformation.(195) Histones also serve as acceptors of ADP-ribose upon DNA damage to initiate DNA repair.”
Erasers of histone acetylation: the histone deacetylase enzymes. (2014, background): “SIRT7 is a highly selective H3K18 deacetylase that plays a key role in cellular transformation (Barber et al. 2012).”
The world of protein acetylation. (2016, background): “Additionally, SIRT7, which is active in the nucleolus, was shown to specifically deacetylate the K18 on histone protein H3 (H3K18Ac), subsequently maintaining tumorigenicity of human cancer cells [224].”