MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment

Nat Commun. 2015 Nov 4;6:8755. doi: 10.1038/ncomms9755.

Abstract

Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-α instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF-stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-α into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITF(low)/c-Jun(high) syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenvironment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITF(low)/c-Jun(high) melanomas to counteract their growth-promoting and immunosuppressive functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Dedifferentiation / genetics*
  • Cell Dedifferentiation / immunology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cytokines / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Inflammation
  • Melanoma / genetics*
  • Melanoma / immunology
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Microphthalmia-Associated Transcription Factor / immunology
  • Myeloid Cells / immunology*
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-jun
  • Real-Time Polymerase Chain Reaction
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / immunology
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Cytokines
  • Microphthalmia-Associated Transcription Factor
  • Proto-Oncogene Proteins c-jun
  • Tumor Necrosis Factor-alpha

Associated data

  • GEO/GSE71798
  • GEO/GSE71881
  • GEO/GSE71886