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

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

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 invivo 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.

Highlights

The DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase involved in central RNA-based processes, such as splicing and translation, and frequently dysregulated in human cancers (Soto-Rifo and Ohlmann, 2013)
The DDX3X Gene Is Somatically Altered in Melanoma Tumors To explore the clinical significance of DDX3X dysfunction in melanoma, we examined the mutational landscape of 864 melanoma tumors
DDX3X mutations were independent of other genetic alterations affecting the BRAF and NRAS genes commonly occurring in melanomas, and a weak association with concurrent NF1 gene mutations was observed (p = 0.02; Fisher’s exact test; Figure 1B; Cancer Genome Atlas Network, 2015)

Summary

Introduction

The DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase involved in central RNA-based processes, such as splicing and translation, and frequently dysregulated in human cancers (Soto-Rifo and Ohlmann, 2013). DDX3X was shown to affect the translation of mRNAs characterized by highly structured 50 UTRs, including those harboring internal ribosome entry sites (IRESs) (Chen et al, 2015; Geissler et al, 2012; Soto-Rifo et al, 2012). The translational changes downstream of DDX3X have been shown to affect the expression of genes important for development and tumorigenesis (Chen et al, 2015, 2016; Lai et al, 2010). Evidence indicates that DDX3X is mutated in different types of human cancer, its role in tumorigenesis remains incompletely understood (Bol et al, 2015). The intrinsic biological explanations of the survival differences are still largely unclear, there are studies suggesting that sex-chromosome-specific genes may play a significant role in disease progression (van Kempen et al, 2016).

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