SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.
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.
Department of Biology, Stanford University, Stanford, California 94305, USA.
Matthew F
MF
Barber
Eriko
E
Michishita-Kioi
Yuanxin
Y
Xi
Luisa
L
Tasselli
Mitomu
M
Kioi
Zarmik
Z
Moqtaderi
Ruth I
RI
Tennen
Silvana
S
Paredes
Nicolas L
NL
Young
Kaifu
K
Chen
Kevin
K
Struhl
Benjamin A
BA
Garcia
Or
O
Gozani
Wei
W
Li
Katrin F
KF
Chua
D000107:Acetylation; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D003260:Contact Inhibition; D018450:Disease Progression; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D059372:Nucleotide Motifs; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D050808:ets-Domain Protein Elk-4 / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D002843:Chromatin; C494193:ELK4 protein, human; D006657:Histones; D012097:Repressor Proteins; C510661:SIRT7 protein, human; D050808:ets-Domain Protein Elk-4; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine