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

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) signa...

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Vydáno v:Cell reports (Cambridge) Ročník 18; číslo 8; s. 1858 - 1868
Hlavní autoři: Ioris, Rafael M., Galié, Mirco, Ramadori, Giorgio, Anderson, Jason G., Charollais, Anne, Konstantinidou, Georgia, Brenachot, Xavier, Aras, Ebru, Goga, Algera, Ceglia, Nicholas, Sebastián, Carlos, Martinvalet, Denis, Mostoslavsky, Raul, Baldi, Pierre, Coppari, Roberto
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 21.02.2017
Cell Press
Elsevier
Témata:
Acetylation
Animals
cancer stemness
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
PI3K
Signal Transduction - physiology
SIRT6
Sirtuins - metabolism
Transcription, Genetic - physiology
PI3K
SIRT6
cancer stemness
ISSN:2211-1247, 2211-1247
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Shrnutí: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. [Display omitted] •Enhanced SIRT6 hinders stemness of human cancer cells with PI3K activation•Enhanced SIRT6 rearranges metabolism of cancer cells with PI3K activation•Enhanced SIRT6 reduces grade and progression of murine tumors with PI3K activation•Anti-cancer-stemness action is independent of SIRT6 histone deacetylase activity Ioris et al. provide in vitro and in vivo evidence that enhanced SIRT6 suppresses cancer progression and stemness in the context of constitutively active PI3K signaling. This effect is, at least in part, through suppression of the PI3K pathway at the transcriptional level and independent of SIRT6’s histone deacetylase activity.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2017.01.065