Heterochromatin Reduction Correlates with the Increase of the KDM4B and KDM6A Demethylases and the Expression of Pericentromeric DNA during the Acquisition of a Transformed Phenotype

Cancer cells have alterations in chromatin organization, mostly a reduction in heterochromatin. How this process occurs during transformation and if it participates in the maintenance of a cancerous phenotype is not well understood. Here, using a transformation-inducible cell line, we analyzed the changes that occur in heterochromatin during transformation to a cancerous phenotype. After transformation, there is a reduction in heterochromatin bodies and a nuclear reorganization of HP1a. These occurrences correlate with reductions in H3K9me3 and H3K27me3 levels and with some of the enzymes that introduce these modifications. At the same time, there are increases in the KDM4B and KDM6A/UTX demethylases and an enhancement in the transcription of pericentromeric DNA that correlate with the reduction of H3K9me3 and the recruitment of KDM4B to these elements. The depletion of KDM4B and KDM6A/UTX has a more deleterious effect in transformed cells than in their progenitors, suggesting an important role for these enzymes in the survival of cancerous cells. These results provide new insights into heterochromatin dynamics during transformation to a cancerous phenotype as well as some of the participating mechanisms.