Harnessing the HDAC–histone deacetylase enzymes, inhibitors and how these can be utilised in tissue engineering

Abstract

There are large knowledge gaps regarding how to control stem cells growth and differentiation. The limitations of currently available technologies, such as growth factors and/or gene therapies has led to the search of alternatives. We explore here how a cell’s epigenome influences determination of cell type, and potential applications in tissue engineering. A prevalent epigenetic modification is the acetylation of DNA core histone proteins. Acetylation levels heavily influence gene transcription. Histone deacetylase (HDAC) enzymes can remove these acetyl groups, leading to the formation of a condensed and more transcriptionally silenced chromatin. Histone deacetylase inhibitors (HDACis) can inhibit these enzymes, resulting in the increased acetylation of histones, thereby affecting gene expression. There is strong evidence to suggest that HDACis can be utilised in stem cell therapies and tissue engineering, potentially providing novel tools to control stem cell fate. This review introduces the structure/function of HDAC enzymes and their links to different tissue types (specifically bone, cardiac, neural tissues), including the history, current status and future perspectives of using HDACis for stem cell research and tissue engineering, with particular attention paid to how different HDAC isoforms may be integral to this field.

Teratoma Growth Retardation by HDACi Treatment of the Tumor Embryonal Source

“…Histone acetylation is primarily regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). There are 18 HDACs that are divided into classes I, II, III and IV, based on their function and sequence similarity [ 20 , 21 , 24 , 25 ]. The use of HDAC inhibitors (HDACi) as therapy for neoplastic diseases is a decades-old idea [ 23 , 26 ] that culminated in the FDA approval of HDACi cancer drugs [ 21 ].…”

“…The use of HDAC inhibitors (HDACi) as therapy for neoplastic diseases is a decades-old idea [ 23 , 26 ] that culminated in the FDA approval of HDACi cancer drugs [ 21 ]. HDACi are small molecules that inhibit the action of HDACs and increase the acetylation levels of histones, thereby producing an effect on a whole variety of biological processes, such as apoptosis, autophagy, senescence, growth arrest, differentiation and cell cycle arrest [ 23 , 24 , 27 ]. In fact, it was shown that in mouse and human TGCT cell lines, HDACi treatment can downregulate stemness genes and promote differentiation [ 21 ].…”

Butyrate Shapes Immune Cell Fate and Function in Allergic Asthma

“…Acetylation of these transcription factors has been reported to regulate their stability, alter protein-protein interactions, affect subcellular localization, and modify transcriptional activating functions. Thus, HDAC modification of these non-histone targets would also be expected to alter cell activity independently (or in conjunction) with regulation of gene expression ( 32 , 33 ). It is not always clear which HDAC isoforms are responsible for direct deacetylation of these targets.…”

“…HDAC inhibitors (HDACi) have a varied effect on cell cycle, differentiation, and cell death (apoptosis, necrosis and autophagy) ( 33 ). The class I isoforms (HDAC1, 2, 3, & 8) are ubiquitously expressed whereas class II isoforms (HDAC4, 5, 6, 7, 9, & 10) and the sole class IV isoform (HDAC11) have more restricted tissue distribution including expression in some immune cell subsets ( 32 , 33 ). Although the activity of class I isoforms is largely (but not completely) restricted to the nucleus, class II and IV isoforms shuttle between the nucleus and cytoplasm.…”

Plant flavone Chrysin as an emerging histone deacetylase inhibitor for prosperous epigenetic‐based anticancer therapy

“…While four HDACs (1/2/3/8) belong to Class I, six HDACs (4, 5, 6, 7, 9 and 10) pertain to Class II. Seven HDACs from SIRT1‐SIRT7 form the Class III, while HDAC11 is the only isoenzyme of Class IV (Figure 1) (Lawlor & Yang, 2019). While in certain cancers multiple HDACs are hyperactive, a single HDAC may have implications in others (Ganai, 2018).…”