STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway

Alexander Swoboda, Robert Soukup, Oliver Eckel, Katharina Kinslechner, Bettina Wingelhofer, David Schörghofer, Christina Sternberg, Ha T.T. Pham, Maria Vallianou, Jaqueline Horvath, Dagmar Stoiber, Lukas Kenner, Lionel Larue, Valeria Poli, Friedrich Beermann, Takashi Yokota, Stefan Kubicek, Thomas Krausgruber, André F. Rendeiro, Christoph BockRainer Zenz, Boris Kovacic, Fritz Aberger, Markus Hengstschläger, Peter Petzelbauer, Mario Mikula*, Richard Moriggl*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

42 Citations (Scopus)

Abstract

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 Stat3 in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed 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 STAT3 in 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 MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. 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 MITF via direct induction of CEBP family member transcription.

Original languageEnglish
Pages (from-to)1091-1105
Number of pages15
JournalOncogene
Volume40
Issue number6
DOIs
Publication statusPublished - 11 Feb 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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