MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma

Oncotarget. 2016 Aug 23;7(34):55128-55140. doi: 10.18632/oncotarget.10422.


The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway is frequently hyper-activated upon vemurafenib treatment of melanoma. We have here investigated the relationship between SRY-box 10 (SOX10), forkhead box 3 (FOXD3) and microphthalmia-associated transcription factor (MITF) in the regulation of the receptor tyrosine-protein kinase ERBB3, and its cognate ligand neuregulin 1-beta (NRG1-beta). We found that both NRG1-beta and ERBB3 mRNA levels were elevated as a consequence of MITF depletion, induced by either vemurafenib or MITF small interfering RNA (siRNA) treatment. Elevation of ERBB3 receptor expression after MITF depletion caused increased activation of the PI3K pathway in the presence of NRG1-beta ligand. Together, our results suggest that MITF may play a role in the development of acquired drug resistance through hyper-activation of the PI3K pathway.

Keywords: ERBB3; MITF; NRG1-beta; PI3K signaling; melanoma.

MeSH terms

  • Cell Line, Tumor
  • Forkhead Transcription Factors / analysis
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Microphthalmia-Associated Transcription Factor / analysis
  • Microphthalmia-Associated Transcription Factor / physiology*
  • Neuregulin-1 / analysis*
  • Phosphatidylinositol 3-Kinases / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-3 / analysis*
  • SOXE Transcription Factors / analysis
  • Signal Transduction / physiology
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Vemurafenib


  • FOXD3 protein, human
  • Forkhead Transcription Factors
  • Indoles
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • NRG1 protein, human
  • Neuregulin-1
  • SOX10 protein, human
  • SOXE Transcription Factors
  • Sulfonamides
  • Vemurafenib
  • Phosphatidylinositol 3-Kinases
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • Proto-Oncogene Proteins c-akt