Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics

Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-& beta; pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs. The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-& beta; signalling pathway.