ABSTRACT
Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers.
Subject(s)
Epithelial Cells/pathology , Epithelial-Mesenchymal Transition/genetics , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Sarcoma/genetics , Sirtuins/genetics , Cell Line, Tumor , Chromatin/genetics , Disease Progression , Epigenesis, Genetic/genetics , Humans , Phenotype , Prognosis , Sarcoma/pathologyABSTRACT
The chromatin regulatory factor SIRT6 plays pivotal roles in metabolism, tumor suppression, and aging biology. Despite the fundamental roles of SIRT6 in physiology and disease, only a handful of molecular and functional interactions of SIRT6 have been reported. Here, we characterize the SIRT6 interactome and identify 80+ novel SIRT6-interacting proteins. The discovery of these SIRT6-associations considerably expands knowledge of the SIRT6 interaction network, and suggests previously unknown functional interactions of SIRT6 in fundamental cellular processes. These include chromatin remodeling, mitotic chromosome segregation, protein homeostasis, and transcriptional elongation. Extended analysis of the SIRT6 interaction with G3BP1, a master stress response factor, uncovers an unexpected role and mechanism of SIRT6 in regulating stress granule assembly and cellular stress resistance.
Subject(s)
Carrier Proteins/metabolism , Protein Interaction Maps , Signal Transduction/genetics , Sirtuins/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Line, Tumor , DNA Helicases , HEK293 Cells , HeLa Cells , Humans , Mice , Poly-ADP-Ribose Binding Proteins , Protein Binding , Proteomics , RNA Helicases , RNA Interference , RNA Recognition Motif Proteins , RNA, Small Interfering , Sirtuins/genetics , Ubiquitin Thiolesterase/geneticsABSTRACT
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.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Histone Deacetylases/metabolism , Histones/metabolism , Lysine/metabolism , Sirtuins/metabolism , Acetylation , Adenovirus E1A Proteins/genetics , Adenovirus E1A Proteins/metabolism , Animals , Base Sequence , Binding Sites , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Chromatin/metabolism , Contact Inhibition , Disease Progression , Humans , Mice , Neoplasm Transplantation , Nucleotide Motifs , Phenotype , Promoter Regions, Genetic , Repressor Proteins/metabolism , Sirtuins/deficiency , Sirtuins/genetics , Transcription, Genetic , Transplantation, Heterologous , ets-Domain Protein Elk-4/metabolismABSTRACT
Despite resveratrol's well-documented health benefits, its mechanism of action remains controversial. In particular, the direct molecular target of resveratrol has been elusive. Park et al. now show that resveratrol directly inhibits cAMP-dependent phosphodiesterases, triggering a cascade of events that converge on the important energy-sensing metabolic regulators AMPK, SIRT1, and PGC-1α.