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

    17 Citations (Scopus)

    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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    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.",
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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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