Directly to content
  1. Publishing |
  2. Search |
  3. Browse |
  4. Recent items rss |
  5. Open Access |
  6. Jur. Issues |
  7. DeutschClear Cookie - decide language by browser settings

SOX5 is involved in balanced MITF regulation in human melanoma cells

Kordaß, Theresa ; Weber, Claudia E. M. ; Oswald, Marcus ; Ast, Volker ; Bernhardt, Mathias ; Novak, Daniel ; Utikal, Jochen ; Eichmüller, Stefan B. ; König, Rainer

In: BMC Medical Genomics, 9 (2016), Nr. 10. pp. 1-15. ISSN 1755-8794

[img]
Preview
PDF, English
Download (1MB) | Lizenz: Creative Commons LizenzvertragSOX5 is involved in balanced MITF regulation in human melanoma cells by Kordaß, Theresa ; Weber, Claudia E. M. ; Oswald, Marcus ; Ast, Volker ; Bernhardt, Mathias ; Novak, Daniel ; Utikal, Jochen ; Eichmüller, Stefan B. ; König, Rainer underlies the terms of Creative Commons Attribution 3.0 Germany

Citation of documents: Please do not cite the URL that is displayed in your browser location input, instead use the DOI, URN or the persistent URL below, as we can guarantee their long-time accessibility.

Abstract

Background: Melanoma is a cancer with rising incidence and new therapeutics are needed. For this, it is necessary to understand the molecular mechanisms of melanoma development and progression. Melanoma differs from other cancers by its ability to produce the pigment melanin via melanogenesis; this biosynthesis is essentially regulated by microphthalmia-associated transcription factor (MITF). MITF regulates various processes such as cell cycling and differentiation. MITF shows an ambivalent role, since high levels inhibit cell proliferation and low levels promote invasion. Hence, well-balanced MITF homeostasis is important for the progression and spread of melanoma. Therefore, it is difficult to use MITF itself for targeted therapy, but elucidating its complex regulation may lead to a promising melanoma-cell specific therapy. Method: We systematically analyzed the regulation of MITF with a novel established transcription factor based gene regulatory network model. Starting from comparative transcriptomics analysis using data from cells originating from nine different tumors and a melanoma cell dataset, we predicted the transcriptional regulators of MITF employing ChIP binding information from a comprehensive set of databases. The most striking regulators were experimentally validated by functional assays and an MITF-promoter reporter assay. Finally, we analyzed the impact of the expression of the identified regulators on clinically relevant parameters of melanoma, i.e. the thickness of primary tumors and patient overall survival. Results: Our model predictions identified SOX10 and SOX5 as regulators of MITF. We experimentally confirmed the role of the already well-known regulator SOX10. Additionally, we found that SOX5 knockdown led to MITF up-regulation in melanoma cells, while double knockdown with SOX10 showed a rescue effect; both effects were validated by reporter assays. Regarding clinical samples, SOX5 expression was distinctively up-regulated in metastatic compared to primary melanoma. In contrast, survival analysis of melanoma patients with predominantly metastatic disease revealed that low SOX5 levels were associated with a poor prognosis. Conclusion: MITF regulation by SOX5 has been shown only in murine cells, but not yet in human melanoma cells. SOX5 has a strong inhibitory effect on MITF expression and seems to have a decisive clinical impact on melanoma during tumor progression.

Item Type: Article
Journal or Publication Title: BMC Medical Genomics
Volume: 9
Number: 10
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 09 Mar 2016 08:04
Date: 2016
ISSN: 1755-8794
Page Range: pp. 1-15
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Medizinische Fakultät Mannheim > Hautklinik
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 610 Medical sciences Medicine
About | FAQ | Contact | Imprint |
OA-LogoDINI certificate 2013Logo der Open-Archives-Initiative