Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

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.

The SIRT6-Autophagy-Warburg Effect Axis in Papillary Thyroid Cancer

“…SIRT6 activated the AMPK pathway by regulating H3K9ac and H3K56ac in podocytes, thus preventing ROS-induced mitochondrial dysfunction and apoptosis (34). Furthermore, SIRT6 promoted autophagy through the ROS-mediated activation of the AMPK pathway in cancer cell lines (35). In the present study, ROS inhibition showed a stronger association with the expression Warburg effect-related genes than AMPK activation.…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…Activator SIRT1 [166,167] No report 4 UBCS039 Activator SIRT5 and SIRT6 [168] Inducing autophagy-associated cell death in cervix, colon and lung cancer [169].…”

CDK5: Key Regulator of Apoptosis and Cell Survival

“…In healthy mammalian cells, the dominant activity is directed towards intracellular homeostatic turnover of proteins, mediating self-renewal energy generation, metabolism, and cell death [104][105][106]. New evidence has reported that many diseases are connected to autophagy, including primary cancer origins [107]. Autophagy activation insures and protects cancer cells, and this process in known as adaptive autophagy, which is directly associated with CDK5.…”