| Autor: |
Swoboda, Alexander, Soukup, Robert, Eckel, Oliver, Kinslechner, Katharina, Wingelhofer, Bettina, Schörghofer, David, Sternberg, Christina, Pham, Ha T. T., Vallianou, Maria, Horvath, Jaqueline, Stoiber, Dagmar, Kenner, Lukas, Larue, Lionel, Poli, Valeria, Beermann, Friedrich, Yokota, Takashi, Kubicek, Stefan, Krausgruber, Thomas, Rendeiro, André F., Bock, Christoph, Zenz, Rainer, Kovacic, Boris, Aberger, Fritz, Hengstschläger, Markus, Petzelbauer, Peter, Mikula, Mario, Moriggl, Richard |
| Zdroj: |
Oncogene; February 2021, Vol. 40 Issue: 6 p1091-1105, 15p |
| Abstrakt: |
Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3in melanocytes with specific expression of human hyperactive NRASQ61Kin an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain, and liver metastases. Whole-genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3in mouse or human cells resulted in the upregulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CAAT Box Enhancer Binding Protein(CEBP)expression was sufficient to suppress MITFtranscription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/bbinding to the MITFenhancer region silenced the MITFlocus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITFvia direct induction of CEBP family member transcription. |
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