SIRT7 links site-specific histone H3 lysine 18 deacetylation to oncogenic transformation programs  

Matthew F. Barber*, Eriko Michishita*, Yuanxin Xi*, Mitomu Kioi, Zarmik Moqtaderi, Ruth I. Tennen, Nicolas L. Young, Kevin Struhl, Benjamin Garcia, Or Gozani, Wei Li# and Katrin F. Chua#

 
 

Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism, and aging. 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 deacetylase with specificity for lysine 18 of histone H3 (H3K18Ac), and is important for maintaining the stability of the cancer cell phenotype. 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 genes with links to tumor suppression. Notably, selective hypoacetyation of H3K18Ac has recently been linked to oncogenic transformation, and in patients, is associated with aggressive tumor phenotypes and poor prognosis1-4. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells such as 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 tumorigenicity 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 tumor formation in vivo.