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

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

Cell Rep. 2017 Feb 21;18(8):1858-1868. doi: 10.1016/j.celrep.2017.01.065.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
⁵ 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.
⁶ 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.
⁷ Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
⁸ 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.
⁹ 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.

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.

Keywords: PI3K; SIRT6; cancer stemness.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Carcinogenesis / metabolism
Cell Line, Tumor
Cell Proliferation / physiology
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Mutation / physiology
Neoplasms / metabolism*
Neoplastic Stem Cells / metabolism*
Phosphatidylinositol 3-Kinases / metabolism*
Signal Transduction / physiology
Sirtuins / metabolism*
Transcription, Genetic / physiology

Substances

Phosphatidylinositol 3-Kinases
SIRT6 protein, human
Sirtuins

Abstract

Publication types

MeSH terms

Substances

Grants and funding