title: The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun.
abstract: Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling-related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling-related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.
authors.affiliation: Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, Chicago, IL, USA.
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.forename: Prabhakaran
authors.initials: P
authors.lastname: Vasudevan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Gene
authors.initials: G
authors.lastname: Kim
authors.forename: Sadhana
authors.initials: S
authors.lastname: Samant
authors.forename: Vishwas
authors.initials: V
authors.lastname: Parekh
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.forename: P V
authors.initials: PV
authors.lastname: Ravindra
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.forename: Valluvan
authors.initials: V
authors.lastname: Jeevanandam
authors.forename: John M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D007334:Insulin-Like Growth Factor I; D056466:Histone Demethylases; C501860:Sirt6 protein, mouse; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases; D037761:Sirtuins