Histone Deacetylases and Histone Deacetylase Inhibitors in Neuroblastoma

Abstract

Histone deacetylases (HDACs) are enzymes that play a key role in regulating gene expression by remodeling chromatin structure. An imbalance of histone acetylation caused by deregulated HDAC expression and activity is known to promote tumor progression in a number of tumor types, including neuroblastoma, the most common solid tumor in children. Consequently, the inhibition of HDACs has emerged as a potential strategy to reverse these aberrant epigenetic changes, and several classes of HDAC inhibitors (HDACi) have been shown to inhibit tumor proliferation, or induce differentiation, apoptosis and cell cycle arrest in neuroblastoma. Further, the combined use of HDACi with other chemotherapy agents, or radiotherapy, has shown promising pre-clinical results and various HDACi have progressed to different stages in clinical trials. Despite this, the effects of HDACi are multifaceted and more work needs to be done to unravel their specific mechanisms of actions. In this review, we discuss the functional role of HDACs in neuroblastoma and the potential of HDACi to be optimized for development and use in the clinic for treatment of patients with neuroblastoma.

A Chemo-Genomic Approach Identifies Diverse Epigenetic Therapeutic Vulnerabilities in MYCN-Amplified Neuroblastoma

“…In addition to signalling previously reported cross-talk between MYCN and HDAC (Lodrini et al, 2013;Duffy et al, 2016;Fabian et al, 2016;Phimmachanh et al, 2020), we revealed novel MYCN-epigenetic interactions, including those with SMARC genes. SMARC genes were identified as inferred transcriptional regulators of MYCN-bound genes (ChIP-seq), their expression showed strong correlation to neuroblastoma outcome, and SMARCA inhibition strongly reduced IMR32 cell viability.…”

The epigenetics of keloids

“…There are hundreds of HDAC inhibitors in development for treatment of cancers, and there is a high chance that one of these could be an excellent candidate to treat keloids. 153 To date, most HDAC inhibitors tested in keloids are pan-HDAC inhibitors, which lack precision and may have unwanted effects. Specific HDAC inhibitors, especially to HDAC2, upregulated in both normal and keloid scars, 23 would be an excellent candidates.…”

Personalized Medicine for Neuroblastoma: Moving from Static Genotypes to Dynamic Simulations of Drug Response

“…Histone acetyltransferases (HATs) add acetyl groups to lysine residues, inducing an “open” chromatin conformation and thus promoting transcription, while histone deactylases (HDACs) remove acetyl groups, condensing chromatin, resulting in transcriptional repression. A number of HDACs are implicated in tumour growth, cell survival and poor patient outcomes in neuroblastoma, while HDAC inhibitors have been extensively studied in numerous malignancies, including neuroblastoma [ 96 ]. As a result, HDAC inhibitors are currently under heavy interrogation in both preclinical and clinical trials.…”

“…Promising results have been documented for numerous other HDAC inhibitors, however as of now, only vorinostat is being studied in phase II clinical trials [ 100 ]. Multiple reviews have recently been published addressing the potential for HDAC inhibition in neuroblastoma treatment [ 96 , 101 , 102 ], underlining HDACs as an attractive and promising target for therapeutic intervention.…”