The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma

Cell Rep. 2019 Jun 18;27(12):3573-3586.e7. doi: 10.1016/j.celrep.2019.05.069.

Abstract

The X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5' UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.

Keywords: DDX3X; IRES; MITF; melanocyte; melanoma; metastasis; migration; resistance; therapy; translation control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cellular Reprogramming*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation*
  • Gene Expression Regulation, Neoplastic*
  • Genes, X-Linked
  • Humans
  • Internal Ribosome Entry Sites
  • Lymphatic Metastasis
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / secondary*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Prognosis
  • Protein Biosynthesis / genetics*

Substances

  • Internal Ribosome Entry Sites
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • DDX3X protein, human
  • DEAD-box RNA Helicases