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Silencing and re-expression of retinoic acid receptor beta2 in human melanoma

Jun Fan1, Linda Eastham, Melinda E Varney

  • 1Department of Biochemistry & Microbiology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.

Pigment Cell & Melanoma Research
|April 9, 2010
PubMed

Insights

Melanoma cells often resist all-trans retinoic acid (ATRA) treatment. Promoter methylation silences the Retinoic Acid Receptor-beta2 (RAR-beta2) gene, hindering ATRA

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Melanoma cells exhibit resistance to the anti-proliferative effects of all-trans retinoic acid (ATRA).
  • Retinoic Acid Receptor-beta2 (RAR-beta2) is a key mediator of ATRA-induced growth inhibition.
  • Expression of RAR-beta2 correlates with ATRA sensitivity in melanoma cells.

Purpose of the Study:

  • To investigate the mechanisms underlying RAR-beta2 silencing in ATRA-resistant melanoma cells.
  • To explore the role of DNA methylation and histone acetylation in regulating RAR-beta2 expression.
  • To identify potential strategies for restoring ATRA sensitivity in melanoma.

Main Methods:

  • Analysis of RAR-beta2 gene expression in melanoma and melanocytes.
  • Assessment of DNA methylation patterns within the RAR-beta gene promoter.
  • Evaluation of global and RARbeta-specific nucleosome repeat length (NRL).
  • Measurement of histone H3 and H4 pan-acetylation within the RAR-beta gene promoter.
  • Treatment with ATRA, phytochemicals, Trichostatin A, and 5-aza-2'-deoxycytidine (5-aza-dC).

Main Results:

  • A correlation was observed between ATRA anti-proliferative activity and RAR-beta2 expression.
  • No strict correlation was found between RAR-beta gene DNA methylation and its expression.
  • Histone H3 and H4 pan-acetylation was higher in RAR-beta2 expressing cells.
  • ATRA treatment increased H4 pan-acetylation in non-responsive cells.
  • 5-aza-dC treatment reactivated RAR-beta2 expression and restored ATRA sensitivity in WM1366 melanoma cells.

Conclusions:

  • Promoter methylation is responsible for RAR-beta2 silencing in a subset of melanoma cells.
  • Histone H3 pan-acetylation appears to play a permissive role in RAR-beta2 gene expression.
  • Reactivation of RAR-beta2 through demethylation could restore ATRA efficacy in melanoma treatment.

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