The balance of histone acetylation is an important epigenetic layer in regulating gene expression. Through the remodelling of chromatin structure by removal of acetyl groups from histones, histone deacetylases (HDACs) are known to alter the transcription of key genes involved in tumorigenesis. Consequently, the inhibition of HDACs has emerged as a potential strategy to reverse these aberrant epigenetic changes. Several classes of HDAC inhibitors (HDACi) have now been shown to elicit anti-cancer effects across a number of tumour types, including neuroblastoma, the most common extracranial solid tumour in children. However, the cellular function of each individual HDAC enzyme is complex, and the effects of HDACi are multifaceted and not well understood. As such, more work is required to unravel their specific mechanisms of action in order to develop rationalised clinical treatment regimens.
Through an integrated single cell analysis combining both therapeutic and genetic inhibition of HDAC family members with established high content imaging assays, we now aim to delineate the precise functions of HDACs and discrete mechanisms of HDACi in neuroblastoma.
This analysis has demonstrated that FDA-approved HDACi, with differing specificity, are capable of eliciting a diverse range of cell behaviour in neuroblastoma tumours. Specifically, treatment with Romidepsin and Panobinostat directly promoted the induction of apoptosis. Whereas the treatment of neuroblastoma cells with Belinostat or Vorinostat did not induce apoptosis, but a cell state that sensitised the cells to subsequent treatment with standard-of-care chemotherapies. These differing functional outcomes were also associated with unique histone acetylation patterns and mechanistically coherent gene expression changes.
These findings highlight the complexity of the HDAC network and the ability of each HDACi to induce their anti-cancer activity by different mechanisms. Future work is aimed at leveraging this mechanistic understanding to ensure that these HDACi can be employed within the most efficacious combinations and clinically relevant treatment schedules, in order to improve patient outcomes for neuroblastoma patients.