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

Ioris, Rafael Maciel; Galiè, Mirco; Ramadori, Giorgio; Anderson, Julie D.; Charollais, Anne; Konstantinidou, Georgia; Brénachot, Xavier; Aras, Ebru; Goga, Algera; Ceglia, Nicholas; Sebastián, Carlos; Martinvalet, Denis; Mostoslavsky, Raúl; Baldi, Pierre; Coppari, Roberto

doi:10.1016/j.celrep.2017.01.065

Cited by 44 publications

(36 citation statements)

References 53 publications

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“…colorectal, breast, ovarian, hepatocellular, lung, and pancreatic tumors) and its downregulation is associated with poor prognosis 16 – 18 . Consistent with these results, loss of SIRT6 leads to tumor formation and maintenance 8 and ectopic expression of SIRT6 inhibits cancer stem cell proliferation 19 , 20 . In other tumors (i.e.…”

Section: Introductionsupporting

confidence: 72%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.

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Section: Introductionsupporting

confidence: 72%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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show abstract

“…Several studies propose that SIRT6 is an attractive target for activation, as it is shown to suppress survival of cancer cells [ 25 , 59 ] and extend longevity in whole body overexpressing mice [ 30 ]. Our data support the role of SIRT6 in the regulation of cell death, but add caution to potential therapies promoting its activity, because it may exacerbate death of DA neurons (among other cell types) and accelerate PD-associated degeneration.…”

Section: Discussionmentioning

confidence: 99%

Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6

Nicholatos

Francisco

Bender

et al. 2018

acta neuropathol commun

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Parkinson’s disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson’s. We report that nicotine reduces the abundance of SIRT6 in neuronal culture and brain tissue. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson’s patient brains, and decreased in the brains of tobacco users. We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson’s. Furthermore, brain-specific SIRT6 knockout mice are protected from MPTP-induced Parkinson’s, while SIRT6 overexpressing mice develop more severe pathology. Our data suggest that SIRT6 plays a pathogenic and pro-inflammatory role in Parkinson’s and that nicotine can provide neuroprotection by accelerating its degradation. Inhibition of SIRT6 may be a promising strategy to ameliorate Parkinson’s and neurodegeneration.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0625-y) contains supplementary material, which is available to authorized users.

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“…ChIP assays were performed as previously described 51 with a few modifications. Cross-linking was obtained with 1% paraformaldehyde for 20 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance

et al. 2017

Self Cite

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Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.

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

Cited by 44 publications

References 53 publications

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6

Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance

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