title: SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity.
abstract: Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation.
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Ioris
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Department of Neurosciences, Biomedicine and Movement, University of Verona, Verona 37134, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Galié
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ramadori
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Anderson
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Charollais
authors.affiliation: Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Georgia
authors.initials: G
authors.lastname: Konstantinidou
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Brenachot
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Ebru
authors.initials: E
authors.lastname: Aras
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Algera
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Computer Science University of California Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ceglia
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastián
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Martinvalet
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: Department of Computer Science University of California Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Baldi
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland. Electronic address: roberto.coppari@unige.ch.
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
mesh_terms: D000107:Acetylation; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D037761:Sirtuins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: PI3K; SIRT6; cancer stemness