Cancer cells are constantly under the pressure of diverse stresses caused either by a specific tumour microenvironment (e.g. nutrient deprivation), or by anticancer treatments (e.g. radiotherapy). To survive, cancer cells must be able to efficiently respond to these challenges to promote their survival. The mechanisms of post-stress recovery in tumour cells are not well understood, but it is well documented that the recovery requires activation of protein biosynthesis and, consequently, the level of ribosome biogenesis (RiBi). The key stage of RiBi is the synthesis of the ribosomal RNA and the available data demonstrate that epigenetic mechanisms play an important role in the regulation of rRNA transcription.
KDM4A is a histone lysine demethylase that is overexpressed in some cancers and can act either as a transcription activator or as a repressor and its pleotropic activity makes it very difficult to comprehensively understand its cellular role. Recently, we discovered a new role for KDM4A in regulating rRNA synthesis by converting “poised” rDNA chromatin to its “active” form during recovery after nutrient deprivation. In subsequent experiments we also found that, similar to starvation, various types of DNA damage and heat shock also led to dissociation of KDM4A from rDNA and its reduced stability correlated with down-regulation of rRNA synthesis. Conversely, KDM4A stabilised and relocalised back to the nucleolus during recovery from a stress, correlating with increased levels of Pol-I transcription.
Here we will discuss the results of our recent experiments suggesting the role of KDM4A in the regulation of the efficiency of post-recovery and our hypothesis that KDM4A is the master regulator that controls the transcription of rRNA, as well as the transcription of other genes on stress dependent manner.