Deemed master regulators of gene expression, histone deacetylases (HDACs) are involved in regulating a number of biological processes through the remodelling of chromatin structure. An imbalance of histone acetylation caused by deregulated HDAC expression and activity is known to promote tumour progression in a number of tumour types, including neuroblastoma, the most common extracranial solid tumour 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 elicit a number of anti-cancer effects in neuroblastoma.
Despite this, the effects of HDACi are multifaceted and more work needs to be done to unravel their specific mechanisms of action in order to develop rationalised clinical treatment regimens. Through an integrated single cell analysis of both therapeutic and genetic inhibition of HDAC family members using a custom siRNA library and a panel of FDA approved HDACi in combination with established high content imaging assays, we will delineate the precise functions of HDACs and discrete mechanisms of HDACi in neuroblastoma.
Our precision-based medicine approach is imperative in developing a rationalised understanding of the functional and therapeutic complexities of this enzyme family that can be used to guide personalised epigenetic drug combinations and improve patient outcomes in neuroblastoma.