Regulation of cellular Cyclin D1 gene by arsenic is mediated through miR-2909

• Arsenic regulates Cyclin ‘D’ gene through miR-2909 induction.
• This miR-2909 initiated a novel cellular genomic-pathway.
• This pathway involved interplay of genes coding for CYLD, KLF4, BCL3 & SP1.

Arsenic through its ability to regulate genes that link cell cycle control with apoptosis has been widely recognized to play a crucial role in oncogenomics. However, the molecular event by which arsenic affects such genes is far from clear. Here we provide reasonably good evidence to support the view that arsenic exposure to human PBMCs (peripheral blood mononuclear cells) at low concentrations results in the over-expression of miR-2909 within these cells. This over-expressed miR-2909 was found to regulate CCND1 (Cyclin D1) gene expression, within these cells by inducing splice-switching of tumor suppresser CYLD (Cylindromatosis) gene as well as modulation of SP1 (Specificity Protein 1) activity through the repression of KLF4 (Kruppel-like factor4) expression at the translational level. Arsenic dependent regulation of AATF (Apoptosis Antagonizing Transcription factor) and BCL3 (B-cell Lymphoma 3) were also found to be modulated through its capacity to induce miR-2909 expression. Based upon these observations, a novel epigenomic pathway was proposed which may not only be useful in understanding the paradoxical role of arsenic in oncogenomics but also may even be useful in devising various strategies for the treatment/prevention of tumors induced by arsenic.