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

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 SchadendorfKristian Pietras, Cristian Bellodi, Göran Jönsson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3573-3586.e7
JournalCell Reports
Issue number12
Publication statusPublished - 2019 Jun 18

Bibliographical note

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Subject classification (UKÄ)

  • Cancer and Oncology
  • Cell and Molecular Biology


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