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

Oncogene. 2021 Feb;40(6):1091-1105. doi: 10.1038/s41388-020-01584-6. Epub 2020 Dec 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Melanocytes / drug effects
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Neoplasm Metastasis
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction / drug effects

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse