A phosphatidylinositol 3-kinase-Pax3 axis regulates Brn-2 expression in melanoma

Mol Cell Biol. 2012 Nov;32(22):4674-83. doi: 10.1128/MCB.01067-12. Epub 2012 Sep 17.

Abstract

Deregulation of transcription arising from mutations in key signaling pathways is a hallmark of cancer. In melanoma, the most aggressive and lethal form of skin cancer, the Brn-2 transcription factor (POU3F2) regulates proliferation and invasiveness and lies downstream from mitogen-activated protein kinase (MAPK) and Wnt/β-catenin, two melanoma-associated signaling pathways. In vivo Brn-2 represses expression of the microphthalmia-associated transcription factor, MITF, to drive cells to a more stem cell-like and invasive phenotype. Given the key role of Brn-2 in regulating melanoma biology, understanding the signaling pathways that drive Brn-2 expression is an important issue. Here, we show that inhibition of phosphatidylinositol 3-kinase (PI3K) signaling reduces invasiveness of melanoma cells in culture and strongly inhibits Brn-2 expression. Pax3, a transcription factor regulating melanocyte lineage-specific genes, directly binds and regulates the Brn-2 promoter, and Pax3 expression is also decreased upon PI3K inhibition. Collectively, our results highlight a crucial role for PI3K in regulating Brn-2 and Pax3 expression, reveal a mechanism by which PI3K can regulate invasiveness, and imply that PI3K signaling is a key determinant of melanoma subpopulation diversity. Together with our previous work, the results presented here now place Brn-2 downstream of three melanoma-associated signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Invasiveness
  • PAX3 Transcription Factor
  • POU Domain Factors / genetics*
  • POU Domain Factors / metabolism
  • Paired Box Transcription Factors / antagonists & inhibitors*
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Promoter Regions, Genetic
  • Protein Binding
  • Signal Transduction / genetics
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Transcription, Genetic
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Homeodomain Proteins
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • POU Domain Factors
  • Paired Box Transcription Factors
  • Phosphoinositide-3 Kinase Inhibitors
  • Wnt Proteins
  • transcription factor Brn-2
  • Mitogen-Activated Protein Kinase Kinases