The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition

The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition

The process by which cells from primary tumors acquire the ability to form distant tumors involves the loss of cell-to-cell adhesion as well as the disruption of the apicobasal polarity, and the transition to a cell type with a more spindle-like morphology. Such changes enable the cells to invade the extracellular matrix. This reversible physiological process is known as the epithelial– mesenchymal transition (EMT or MET in reverse).

The molecular mechanisms underlying EMT include decreased expression of a set of epithelial genes with the concomitant activation of a set of mesenchymal genes, the expression of matrix metalloproteinases markers and the formation of lamellipodia, filopodia and invadopodia. Changes in chromatin configuration have emerged as key to EMT-related transcription factor regulation1, but some of these changes still call for further characterization.

While the four nucleosome histone families provide equal numbers of molecules to the nucleosome, several of the families include multiple variants, whose stoichiometry can vary due to cell type and growth state among other factor. Altered expression of variants in several histone families, including H2A has been associated with cancer. Recently, it has been reported that histone H2A variant macroH2A is a critical component of chromatin that suppresses the progression of melanoma.

Histone H2A.X also belongs to the histone H2A family. Like other histone variants, H2A.X is highly conserved among species and achieves critical cellular functions beyond those fulfilled by canonical H2As. H2A.X plays essential roles in DNA double strand break repair and genome stability, and is classified as a tumor suppressor. As with other H2A variants, the relative amount of H2A.X varies among cell lines. How this variation may affect the transcription regulation of other genes remains poorly investigated.

While comparing growth characteristics of H2A.X-null cells with parental lines, authors observed that the null cells exhibited elevated levels of migration and invasion, characteristic of the EMT transition. Given these observations and the increasing evidence for the role of other histone variants in the regulation of gene transcription and cancer progression, researchers hypothesized that the downregulation of histone variant H2A.X may contribute to the alteration of chromatin configuration and induce changes in cancer gene expression.

Their novel findings provide evidence that H2A.X depletion activates the EMT programme in at least some human colorectal adenocarcinoma cells. The loss of H2A.X was strongly correlated with the EMT-inducing transcription factors Slug and ZEB1 in these cells.

These correlations were substantiated by the observations that the silencing of Slug and ZEB1 abrogated the mesenchymal phenotype exhibited by H2A.X depleted cells. Most importantly, restored expression of H2A.X at least partially reversed the EMT programme induced by H2A.X loss.

H2A.X-deficient cells are proliferation defective, and sensitive to environmental and genotoxic stresses; characteristics which may counteract their increased invasiveness and account for the lack of enhanced metastasis in vivo compared with parental cells. However, in the H2A.X revertants, proliferation is enhanced, but sufficient invasiveness may remain to result in elevated numbers of metastatic lung foci.

Taken together, these results demonstrate that H2A.X may be a novel regulator of the EMT programme and suggest a role for H2A.X in cancer progression and metastasis.