Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9

Abstract

Understanding how an epigenetic regulator drives different cellular responses can be a tricky task. Very often, their activities are modulated by large multiprotein complexes, the composition of which is context- and time-dependent. As a consequence, experiments aimed to unveil the functions of an epigenetic regulator can provide different outcomes and conclusions, depending on the circumstances. HDAC9 (histone deacetylase), an epigenetic regulator that influences different differentiating and adaptive responses, makes no exception. Since its discovery, different phenotypes and/or dysfunctions have been observed after the artificial manipulation of its expression. The cells and the microenvironment use multiple strategies to control and monitor HDAC9 activities. To date, some of the genes under HDAC9 control have been identified. However, the exact mechanisms through which HDAC9 can achieve all the different tasks so far described, remain mysterious. Whether it can assemble into different multiprotein complexes and how the cells modulate these complexes is not clearly defined. In summary, despite several cellular responses are known to be affected by HDAC9, many aspects of its network of interactions still remain to be defined.

Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

“…HDAC9 has also been implicated in providing support for immune and metabolic processes and for protection of the nervous system, among other activities. HDAC9-mediated immune and metabolic dysregulations have been linked to pathological processes associated with human diseases, as recently reviewed by Hu et al [36] and Brancolini et al [36,47]. Below, we will focus on our current understanding of the function of HDAC9 and its role(s) in several major important physiological processes (summarized in Table 2; Fig.…”

“…Post-translational phosphorylation may also modulate the activity of HDAC9 by controlling its subcellular localization [12]. In their recent review, Brancolini et al [36] presented a simplified diagram showing the main domains of HDAC9 that contain phosphorylation sites. The subcellular localization of HDAC9 is controlled by the phosphorylation of at least three serine residues in HDAC9 (Ser220, Ser451 and Ser611) that facilitate binding interactions with dimers of 14-3-3 molecular chaperone proteins [14].…”

Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription

“…In contrast, deletion of HDAC4 and of HDAC9 strongly affects cell survival and proliferation ( 19 , 36 ). The role of these epigenetic regulators, as scaffolds for the assembly of multiprotein complexes, may explain this discrepancy ( 64 , 65 ). Catalytic domain targeting may not be sufficient to knock down all class IIa activities.…”

The Long Non-Coding RNA SNHG12 as a Mediator of Carboplatin Resistance in Ovarian Cancer via Epigenetic Mechanisms

“…Co-expression networks demonstrate that SNHG12 is correlated with genes encoding transcriptional activators such as SP1 (Sp1 transcription factor), MYC (MYC proto-oncogene, bHLH transcription factor), and STAT2 (signal transducer and activator of transcription 2) in OC and predict interactions between SNHG12 and HDACI9 protein by Cross-Linking and ImmunoPrecipitation (CLIP) experiments [ 49 , 85 , 86 ]. The HDAC9 (histone deacetylase 9) gene is overexpressed in cancer cells and is a member of a family of enzymes responsible for the deacetylation of lysine residues, a key event in the aberrant epigenetic repression in cancer [ 87 ]. Other SNHG genes, including DANCR (former SNHG13 ), SNHG14 , and SNHG15, act synergistically with EZH2 (a histone methylase and catalytic subunit of the Polycomb Repressive Complex 2) to inhibit the expression of downstream target genes in endocrine-related cancers [ 69 ].…”