SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity

Rafael M. Ioris; Mirco Galié; Giorgio Ramadori; Jason G. Anderson; Anne Charollais; Georgia Konstantinidou; Xavier Brenachot; Ebru Aras; Algera Goga; Nicholas Ceglia; Carlos Sebastián; Denis Martinvalet; Raul Mostoslavsky; Pierre Baldi; Roberto Coppari

doi:10.1016/j.celrep.2017.01.065

Cell Reports (Feb 2017)

SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity

Rafael M. Ioris,
Mirco Galié,
Giorgio Ramadori,
Jason G. Anderson,
Anne Charollais,
Georgia Konstantinidou,
Xavier Brenachot,
Ebru Aras,
Algera Goga,
Nicholas Ceglia,
Carlos Sebastián,
Denis Martinvalet,
Raul Mostoslavsky,
Pierre Baldi,
Roberto Coppari

Affiliations

Rafael M. Ioris: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Mirco Galié: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Giorgio Ramadori: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Jason G. Anderson: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Anne Charollais: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Georgia Konstantinidou: Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland
Xavier Brenachot: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Ebru Aras: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Algera Goga: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Nicholas Ceglia: Department of Computer Science University of California Irvine, Irvine, CA 92697, USA
Carlos Sebastián: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
Denis Martinvalet: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland
Raul Mostoslavsky: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
Pierre Baldi: Department of Computer Science University of California Irvine, Irvine, CA 92697, USA
Roberto Coppari: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland

DOI: https://doi.org/10.1016/j.celrep.2017.01.065
Journal volume & issue: Vol. 18, no. 8
pp. 1858 – 1868

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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