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Maria Eugenia Cordero Concha

Biomedical analyst

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

Author

  • Bengt Phung
  • Maciej Cieśla
  • Adriana Sanna
  • Nicola Guzzi
  • Giulia Beneventi
  • Phuong Cao Thi Ngoc
  • Martin Lauss
  • Rita Cabrita
  • Eugenia Cordero
  • Ana Bosch
  • Frida Rosengren
  • Jari Häkkinen
  • Klaus Griewank
  • Annette Paschen
  • Katja Harbst
  • Håkan Olsson
  • Christian Ingvar
  • Ana Carneiro
  • Hensin Tsao
  • Dirk Schadendorf
  • Kristian Pietras
  • Cristian Bellodi
  • Göran Jönsson

Summary, in English

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.

Department/s

  • Melanoma Genomics
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • RNA and Stem Cell Biology
  • Experimental oncology
  • Molecular therapeutics in breast cancer
  • Breastcancer-genetics
  • Lund Melanoma Study Group
  • EpiHealth: Epidemiology for Health
  • Surgery (Lund)

Publishing year

2019-06-18

Language

English

Pages

7-3586

Publication/Series

Cell Reports

Volume

27

Issue

12

Document type

Journal article

Publisher

Cell Press

Topic

  • Cancer and Oncology
  • Cell and Molecular Biology

Status

Published

Research group

  • Melanoma Genomics
  • RNA and Stem Cell Biology
  • Experimental oncology
  • Molecular therapeutics in breast cancer
  • Lund Melanoma Study Group

ISBN/ISSN/Other

  • ISSN: 2211-1247