FBXW7 regulates a mitochondrial transcription program by modulating MITF

Pigment Cell Melanoma Res. 2018 Sep;31(5):636-640. doi: 10.1111/pcmr.12704. Epub 2018 Apr 29.

Abstract

FBXW7 is well characterized as a tumor suppressor in many human cancers including melanoma; however, the mechanisms of tumor-suppressive function have not been fully elucidated. We leveraged two distinct RNA sequencing datasets: human melanoma cell lines (n = 10) with control versus silenced FBXW7 and a cohort of human melanoma tumor samples (n = 51) to define the transcriptomic fingerprint regulated by FBXW7. Here, we report that loss of FBXW7 enhances a mitochondrial gene transcriptional program that is dependent on MITF in human melanoma and confers poor patient outcomes. MITF is a lineage-specific master regulator of melanocytes and together with PGC-1alpha is a marker for melanoma subtypes with dependence for mitochondrial oxidative metabolism. We found that inactivation of FBXW7 elevates MITF protein levels in melanoma cells. In vitro studies examining loss of FBXW7 and MITF alone or in combination showed that FBXW7 is an upstream regulator for the MITF/PGC-1 signaling.

Keywords: FBXW7; MITF; PGC-1alpha; melanoma; metabolism; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Melanocytes / metabolism
  • Melanocytes / pathology
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Prognosis
  • Signal Transduction
  • Survival Rate
  • Transcription, Genetic

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha