Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation

Taylor J. Jensen, Ryan J. Wozniak, Kylee E. Eblin, Sean M. Wnek, A Jay Gandolfi, Bernard W Futscher

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Arsenic is a human carcinogen with exposure associated with cancer of the lung, skin, and bladder. Many potential mechanisms have been implicated as playing a role in the process of arsenical-induced malignancy including the perturbation of signaling pathways and aberrant epigenetic regulation. We initiated studies to examine the role of a member of the non-canonical WNT signaling pathway, WNT5A, in UROtsa cells and arsenite [URO-ASSC] and monomethylarsonous acid [URO-MSC] malignantly transformed variants. We present data herein that suggest that WNT5A is transcriptionally activated during arsenical-induced malignant transformation. This WNT5A transcriptional activation is correlated with the enrichment of permissive histone modifications and the reduction of repressive modifications in the WNT5A promoter region. The epigenetic activation of WNT5A expression and acetylation of its promoter remain after the removal of the arsenical, consistent with the maintenance of an anchorage independent growth phenotype in these cells. Additionally, treatment with epigenetic modifying drugs supports a functional role for these epigenetic marks in controlling gene expression. Reduction of WNT5A using lentiviral shRNA greatly attenuated the ability of these cells to grow in an anchorage independent fashion. Extension of our model into human bladder cancer cell lines indicates that each of the cell lines examined also express WNT5A. Taken together, these data suggest that the epigenetic remodeling of the WNT5A promoter is correlated with its transcriptional activation and this upregulation likely participates in arsenical-induced malignant transformation.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalToxicology and Applied Pharmacology
Volume235
Issue number1
DOIs
StatePublished - Feb 15 2009

Fingerprint

Arsenicals
Epigenomics
Transcriptional Activation
Chemical activation
Urinary Bladder Neoplasms
Cells
Acetylation
Histone Code
Arsenic
Cell Line
Genetic Promoter Regions
Gene expression
Carcinogens
Histones
Small Interfering RNA
Skin Neoplasms
Skin
Lung Neoplasms
Up-Regulation
Maintenance

Keywords

  • Arsenic
  • Epigenetic
  • Histone modification
  • UROtsa
  • WNT5A

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation. / Jensen, Taylor J.; Wozniak, Ryan J.; Eblin, Kylee E.; Wnek, Sean M.; Gandolfi, A Jay; Futscher, Bernard W.

In: Toxicology and Applied Pharmacology, Vol. 235, No. 1, 15.02.2009, p. 39-46.

Research output: Contribution to journalArticle

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