title: Specific c-Jun target genes in malignant melanoma.
abstract: A fundamental event in the development and progression of malignant melanoma is the de-regulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of melanoma progression and, thus, is the most important member of the AP-1 transcription factor family in this disease. Surprisingly, no cancer-related specific c-Jun target genes in melanoma were described in the literature, so far. Therefore, we focused on pre-existing ChIP-Seq data (Encyclopedia of DNA Elements) of 3 different non-melanoma cell lines to screen direct c-Jun target genes. Here, a specific c-Jun antibody to immunoprecipitate the associated promoter DNA was used. Consequently, we identified 44 direct c-Jun targets and a detailed analysis of 6 selected genes confirmed their deregulation in malignant melanoma. The identified genes were differentially regulated comparing 4 melanoma cell lines and normal human melanocytes and we confirmed their c-Jun dependency. Direct interaction between c-Jun and the promoter/enhancer regions of the identified genes was confirmed by us via ChIP experiments. Interestingly, we revealed that the direct regulation of target gene expression via c-Jun can be independent of the existence of the classical AP-1 (5´-TGA(C/G)TCA-3´) consensus sequence allowing for the subsequent down- or up-regulation of the expression of these cancer-relevant genes. In summary, the results of this study indicate that c-Jun plays a crucial role in the development and progression of malignant melanoma via direct regulation of cancer-relevant target genes and that inhibition of direct c-Jun targets through inhibition of c-Jun is a potential novel therapeutic option for treatment of malignant melanoma.
authors.affiliation: a Institute of Biochemistry (Emil-Fischer Center), Friedrich-Alexander University Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schummer
authors.affiliation: a Institute of Biochemistry (Emil-Fischer Center), Friedrich-Alexander University Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kuphal
authors.affiliation: b Department of Biochemistry and Molecular Biology , Tel Aviv University , Israel.
authors.forename: Lily
authors.initials: L
authors.lastname: Vardimon
authors.affiliation: a Institute of Biochemistry (Emil-Fischer Center), Friedrich-Alexander University Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
authors.affiliation: a Institute of Biochemistry (Emil-Fischer Center), Friedrich-Alexander University Erlangen-Nürnberg , Erlangen , Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kappelmann
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*
chemical_list: D016755:Proto-Oncogene Proteins c-jun
keywords: AP-1; ChIP-Seq; Chromatin-immunoprecipitation (ChIP); c-Jun; malignant melanoma; regulatory mechanisms; transcription factors