From HDACi to KDACi: we need to revisit non‐epigenetic pathways affected by inhibiting lysine deacetylases in therapy

Abstract

Lysine deacetylases act on many other proteins apart from histones, with effects on metabolism and gene expression. We need to be cautious that therapeutically used KDACi have a much more widespread impact than anticipated.

Various human maladies during aging are associated with substantial transcriptomic deregulation. Such widespread alterations of gene expression are thought to be mediated, at least partially, by changes in histone modifications. Large amount of data suggest that changes in histone acetylation levels are associated with severe diseases as well as aging 1. Drugs that target and reverse the deregulated histone acetylation sites have therefore attracted considerable attention in recent years as an efficient approach for epigenetic therapy 1, 2. Indeed, previous studies suggested that administrating histone deacetylase inhibitors could serve as a therapeutic avenue in age‐associated maladies by transcriptional reprogramming 2.

There is increasing evidence that lysine acetylation also modifies multiple non‐histone proteins and may be causally associated with several diseases or degenerative processes during aging 3, 4. Although the function of most non‐histone acetylation remains poorly understood in vivo, lysine acetylation regulates several pathways, including non‐histone‐mediated transcription. Furthermore, lysine acetylation has been shown to regulate the activity, localization, protein–protein interactions, and stability of proteins 4, 5. A recent study demonstrated that treatment of human cell lines with various (K) lysine deacetylase inhibitors (KDACi) modulates the acetylation levels of hundreds of proteins, including transcription factors and metabolic enzymes, suggesting that their effect is much more widespread than previously anticipated 6. It is therefore plausible that the administration of KDACi may impact gene expression via increasing the acetylation of transcription factors, rather than solely the histones 4.

Interestingly, the impact of administrating inhibitors for non‐sirtuin KDACs on metabolic activity remains largely underexplored. Chronic treatment of the KDACi/metabolite sodium butyrate in mice was shown to improve metabolism and reduce muscle loss, although the exact mechanism remains unclear 7. In addition, acute treatment of tissue from Drosophila melanogaster with the KDAC inhibitors trichostatin A or sodium butyrate results in a rapid and transient increase in oxygen consumption 8. These results suggest a novel mechanism by which KDAC inhibitors transiently increase metabolism independently of gene expression but rather via protein acetylation. It is therefore possible that the therapeutic benefits of KDACi‐mediated epigenetic alterations are achieved, at least in part, via the effect of KDACi on metabolism. Intriguingly, as histone acetylation is tightly regulated by the availability of acetyl‐CoA, it is possible that the increased histone acetylation observed by KDACi treatment is further enhanced by its stimulatory effect on metabolism 4, 8. This is further supported by the notion that the activity and stabilization of several metabolic enzymes involved in the regulation of cellular acetyl‐CoA pool are regulated by acetylation or by KDAC levels 5, 9.

Considering the growing data supporting such alternative mechanisms by which KDACi might achieve therapeutic benefits, future studies may revise the role of KDACi treatment as a purely epigenetic therapy. Given that KDACi might alter cellular metabolic activity and other pathways, chronic administration of KDACi can therefore result in yet‐unknown side effects. Further experiments are therefore required to elucidate the cellular mechanisms that are affected by KDACi to pave the way for precise long‐term therapeutic strategies.