BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells

Lisa Ellmann, Manjunath B. Joshi, Therese J. Resink, Anja K. Bosserhoff, Silke Kuphal

Research output: Contribution to journalArticle

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Abstract

T-cadherin (cadherin 13, H-cadherin, gene name CDH13) has been proposed to act as a tumor-suppressor gene as its expression is significantly diminished in several types of carcinomas, including melanomas. Allelic loss and promoter hypermethylation have been proposed as mechanisms for silencing of CDH13. However, they do not account for loss of T-cadherin expression in all carcinomas, and other genetic or epigenetic alterations can be presumed. The present study investigated transcriptional regulation of CDH13 in melanoma. Bioinformatical analysis pointed to the presence of known BRN2 (also known as POU3F2 and N-Oct-3)-binding motifs in the CDH13 promoter sequence. We found an inverse correlation between BRN2 and T-cadherin protein and transcript expression. Reporter gene analysis and electrophoretic mobility shift assays in melanoma cells demonstrated that CDH13 is a direct target of BRN2 and that BRN2 is a functional transcriptional repressor of CDH13 promoter activity. The regulatory binding element of BRN2 was located-219 bp of the CDH13 promoter proximal to the start codon and was identified as 5′-CATGCAAAA-3′. Ectopic expression of BRN2 in BRN2-negative/T-cadherin-positive melanoma cells resulted in suppression of CDH13 promoter activity, whereas BRN2 knockdown in BRN2-positive/T-cadherin-negative melanoma cells resulted in re-expression of T-cadherin transcripts and protein. Transcriptional repression of CDH13 by BRN2 may participate in malignant transformation of melanoma by increasing invasion and migration potentials of melanoma cells. The study has identified CDH13 as a novel direct BRN2 transcriptional target gene and has advanced knowledge of mechanisms underlying loss of T-cadherin expression in melanoma.

Original languageEnglish
Pages (from-to)1788-1800
Number of pages13
JournalLaboratory Investigation
Volume92
Issue number12
DOIs
Publication statusPublished - 12-2012

Fingerprint

Melanoma
Carcinoma
Initiator Codon
H-cadherin
Loss of Heterozygosity
Electrophoretic Mobility Shift Assay
Tumor Suppressor Genes
Reporter Genes
Epigenomics
Genes
Names
Proteins

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Ellmann, Lisa ; Joshi, Manjunath B. ; Resink, Therese J. ; Bosserhoff, Anja K. ; Kuphal, Silke. / BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells. In: Laboratory Investigation. 2012 ; Vol. 92, No. 12. pp. 1788-1800.
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BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells. / Ellmann, Lisa; Joshi, Manjunath B.; Resink, Therese J.; Bosserhoff, Anja K.; Kuphal, Silke.

In: Laboratory Investigation, Vol. 92, No. 12, 12.2012, p. 1788-1800.

Research output: Contribution to journalArticle

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