• The tumor suppressor phosphatase and tensin homolog protein (PTEN) is negatively regulated by NF-κb p50 homodimers and involves histone 3 methylation/deacetylation in UROtsa cells chronically exposed to monomethylarsonous acid

      Oliva-González, C.; Uresti-Rivera, E.E.; Galicia-Cruz, O.G.; Jasso-Robles, F.I.; Gandolfi, A.J.; Escudero-Lourdes, C.; Univ Arizona, Dept Pharmacol & Toxicol (ELSEVIER IRELAND LTD, 2017-10-05)
      UROtsa cells have been accepted as a model to study carcinogenicity mechanisms of arsenic-associated human bladder cancer. In vitro continuous exposure to monomethylarsonous acid (MMA(III)), leads UROtsa cells to commit to malignant transformation. In this process, NF-kappa beta-associated inflammatory response seems to play an important role since this transcription factor activates some minutes after cells are exposed in vitro to MMA(III) and keeps activated during the cellular malignant transformation. It is known that a slight decrease in the protein phosphatase and tensin homologue (PTEN) gene expression is enough for some cells to become malignantly transformed. Interestingly, this tumor suppressor has been proven to be negatively regulated by NF-kappa beta through binding to its gene promoter. Based on these observations we propose that NF-kappa beta may be involved in arsenic associated carcinogenesis through the negative regulation of PTEN gene expression. Changes in PTEN expression and the binding of p50 NF-kappa beta subunit to PTEN promoter were evaluated in UROtsa cells exposed for 4, 12, 20, or 24 wk to 50 nM MMA(III). Results showed that MMA(III) induced a significant decrease in PTEN expression around 20 wk exposure to MMA(III), which correlated with increased binding of p50 subunit to the PTEN promoter. Consistent with these results, ChIP assays also showed a significant decrease in H3 acetylation (H3ac) but an increase in the repression marks H3k9me3 and H327me3 in PTEN promoter when compared with not treated cells. These results suggest that the activation of NF-kappa beta by MMA(III) may participate in UROtsa cells malignant transformation through the negative regulation of PTEN expression involving p50 homodimers-mediated chromatin remodeling around the PTEN promoter.