Oncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1

Nityanand Maddodi, Kumar M.R. Bhat, Sulochana Devi, Su Chun Zhang, Vijayasaradhi Setaluri

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

MAP2 is a neuron-specific microtubule-associated protein that binds and stabilizes dendritic microtubules. Previously, we showed that MAP2 expression is (a) activated in cutaneous primary melanoma and (b) inversely associated with melanoma tumor progression. We also showed that ectopic expression of MAP2 in metastatic melanoma cells inhibits cell growth by inducing mitotic spindle defects and apoptosis. However, molecular mechanisms of regulation of MAP2 gene expression in melanoma are not understood. Here, we show that in melanoma cells MAP2 expression is induced by the demethylating agent 5-aza-2′-cytidine, and MAP2 promoter is progressively methylated during melanoma progression, indicating that epigenetic mechanisms are involved in silencing of MAP2 in melanoma. In support of this, methylation of MAP2 promoter DNA in vitro inhibits its activity. Because MAP2 promoter activity levels in melanoma cell lines also correlated with activating mutation in BRAF, a gene that is highly expressed in neurons, we hypothesized that BRAF signaling is involved in MAP2 expression. We show that hyperactivation of BRAF-MEK signaling activates MAP2 expression in melanoma cells by two independent mechanisms, promoter demethylation or down-regulation of neuronal transcription repressor HES1. Our data suggest that BRAF oncogene levels can regulate melanoma neuronal differentiation and tumor progression.

Original languageEnglish
Pages (from-to)242-254
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number1
DOIs
Publication statusPublished - 01-01-2010
Externally publishedYes

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Differentiation Antigens
Transcription
Neurons
Tumors
Melanoma
Down-Regulation
Cytidine
Methylation
Microtubule-Associated Proteins
Mitogen-Activated Protein Kinase Kinases
Cell growth
Gene expression
Genes
Cells
Apoptosis
Defects
DNA
Spindle Apparatus
Gene Expression Regulation
Oncogenes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Maddodi, Nityanand ; Bhat, Kumar M.R. ; Devi, Sulochana ; Zhang, Su Chun ; Setaluri, Vijayasaradhi. / Oncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 1. pp. 242-254.
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Oncogenic BRAFV600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and down-regulation of transcription repressor HES1. / Maddodi, Nityanand; Bhat, Kumar M.R.; Devi, Sulochana; Zhang, Su Chun; Setaluri, Vijayasaradhi.

In: Journal of Biological Chemistry, Vol. 285, No. 1, 01.01.2010, p. 242-254.

Research output: Contribution to journalArticle

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