Mutated MITF-E87R in Melanoma Enhances Tumor Progression via S100A4
| Autor: | Shivang Parikh, Abdel G. Elkahloun, Justine Del Rio, Gal Yankovitz, Julia C. Cronin, Todd D. Pricket, Tami Golan, Yuval Tabach, Carmit Levy, Sapir Labes, Mehdi Khaled, Hagar Malcov, Alice Nordlinger, Laetitia Thomas, Elisa Stubbs, Yardena Samuels, Shani Dror |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Skin Neoplasms Mutant DNA Mutational Analysis Immunoblotting Dermatology Melanocyte Biology Biochemistry 03 medical and health sciences medicine Tumor Cells Cultured Humans S100 Calcium-Binding Protein A4 Molecular Biology Melanoma Microphthalmia-Associated Transcription Factor integumentary system Wild type Cell Biology DNA Neoplasm medicine.disease Microphthalmia-associated transcription factor Phenotype body regions Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Tumor progression Mutation Cancer research Disease Progression Chromatin immunoprecipitation |
| Zdroj: | The Journal of investigative dermatology. 138(10) |
| ISSN: | 1523-1747 |
| Popis: | Melanoma, a melanocyte origin neoplasm, is the most lethal type of skin cancer, and incidence is increasing. Several familial and somatic mutations have been identified in the gene encoding the melanocyte lineage master regulator, MITF; however, the neoplastic mechanisms of these mutant MITF variants are mostly unknown. Here, by performing unbiased analysis of the transcriptomes in cells expressing mutant MITF, we identified calcium-binding protein S100A4 as a downstream target of MITF-E87R. By using wild-type and mutant MITF melanoma lines, we found that both endogenous wild-type and MITF-E87R variants occupy the S100A4 promoter. Remarkably, whereas wild-type MITF represses S100A4 expression, MITF-E87R activates its transcription. The opposite effects of wild-type and mutant MITF result in opposing cellular phenotypes, because MITF-E87R via S100A4 enhanced invasion and reduced adhesion in contrast to wild-type MITF activity. Finally, we found that melanoma patients with altered S100A4 expression have poor prognosis. These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability. These data suggest new opportunities for diagnosis and treatment of metastatic melanoma. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|