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Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells. | LitMetric

AI Article Synopsis

  • - SIRT6, a member of the deacetylase sirtuin family, is important in cancer for regulating functions like DNA repair, telomere integrity, and autophagy.
  • - The synthetic compound UBCS039 activates SIRT6, leading to increased autophagy in human tumor cell lines through a mechanism reliant on SIRT6's deacetylating activity and elevated reactive oxygen species (ROS) levels.
  • - Sustained SIRT6 activation by UBCS039 can trigger autophagy-related cell death, indicating potential for this compound in cancer treatment by enhancing autophagic processes.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155207PMC
http://dx.doi.org/10.1038/s41419-018-1065-0DOI Listing

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