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The epigenetic regulation of gene expression is controlled by various processes, of which one is histone acetylation. Many proteins control gene expression via histone acetylation. Those proteins include sirtuins (SIRTs) and bromodomain and extraterminal proteins (BETs), which are known to regulate same cellular processes and pathways. The aim of this study was to explore BET inhibitors' effects on SIRT1. Previously we showed that BET inhibitor (+)-JQ1 increases SIRT1 levels, but in the current study we used also other, structurally diverse BET inhibitors, I-BET151 and Pfi-1, and examined their effects on SIRT1 levels in two breast cancer cell lines. The results differed between the inhibitors and also between the cell lines. (+)-JQ1 had opposite effects on SIRT1 levels in the two cell lines, I-BET151 increased the levels in both cell lines, and Pfi-1 had no effect. In conclusion, the effect of structurally diverse BET inhibitors on SIRT1 levels is divergent, and the responses might also be cell type-dependent. These findings are important for all SIRT1 and BET inhibitor-related research, and they show that different BET inhibitors might have important individual effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Insulin resistance is a characteristic finding in hyperglycaemia and type 2 diabetes. SIRT1 is a NAD + dependent deacetylase that plays a central role in glucose homeostasis and energy metabolism. SIRT1 activators, including plant polyphenols such as resveratrol, improve insulin sensitivity in skeletal muscle tissue. We hypothesised that the novel plant-derived compounds, strigolactone and pinosylvin, beneficially enhance SIRT1 function, insulin signalling, glucose uptake, and mitochondrial biogenesis in skeletal muscle cells. Rat L6 skeletal muscle myotubes were treated with strigolactone analogue GR24 and pinosylvin. Resveratrol was included in experiments as a reference compound. We measured the effects of these compounds on SIRT1 function, insulin signalling, glucose uptake, mitochondrial biogenesis and gene expression profiles. Strigolactone GR24 upregulated and activated SIRT1 without activating AMPK, enhanced insulin signalling, glucose uptake, GLUT4 translocation and mitochondrial biogenesis. Pinosylvin activated SIRT1 in vitro and stimulated glucose uptake through the activation of AMPK. The regulation of SIRT1 by strigolactone GR24 and the activation of AMPK by pinosylvin may offer novel therapeutic approaches in the treatment of insulin resistance in skeletal muscle.

Control of histone acetylation is a part of the epigenetic mechanism that regulates gene expression and chromatin architecture. The members of the bromodomain and extra terminal domain (BET) protein family are a group of epigenetic readers that recognize histone acetylation, whereas histone deacetyl- ases such as sirtuin 1 (SIRT1) function as epigenetic erasers. We observed that BET inhibition by the specific inhibitor JQ1 upregulated SIRT1 expression and activated SIRT1. Moreover, we observed that BET inhibition functionally reversed the pro-inflammatory effect of SIRT1 inhibition in a cellular lung disease model. SIRT1 activation is desirable in many age-related, metabolic and inflammatory diseases; our results suggest that BET protein inhibition would be beneficial in treatment of those conditions. Most importantly, our findings demonstrate a novel mechanism of SIRT1 activation by inhibition of the BET proteins., (© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The modulation of protein deacetylase SIRT1 has a vast therapeutic potential in treatment of several aging-associated diseases. Active regulator of SIRT1 (AROS) is a small endogenous protein which was originally reported to activate SIRT1 through a direct interaction in cancer cells. We show that the interaction between the two proteins is weak and does not alter the activity of SIRT1 in non-cancerous human cells. The results of different in vitro SIRT1 activity assays disclosed AROS as an inhibitor of SIRT1. The functional relationship between AROS and SIRT1 proved to be dependent on the biological context and experimental setting., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)