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

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T1 - The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma

AU - Phung, Bengt

AU - Cieśla, Maciej

AU - Sanna, Adriana

AU - Guzzi, Nicola

AU - Beneventi, Giulia

AU - Cao Thi Ngoc, Phuong

AU - Lauss, Martin

AU - Cabrita, Rita

AU - Cordero, Eugenia

AU - Bosch, Ana

AU - Rosengren, Frida

AU - Häkkinen, Jari

AU - Griewank, Klaus

AU - Paschen, Annette

AU - Harbst, Katja

AU - Olsson, Håkan

AU - Ingvar, Christian

AU - Carneiro, Ana

AU - Tsao, Hensin

AU - Schadendorf, Dirk

AU - Pietras, Kristian

AU - Bellodi, Cristian

AU - Jönsson, Göran

N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2019/6/18

Y1 - 2019/6/18

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2019.05.069

DO - 10.1016/j.celrep.2019.05.069

M3 - Article

VL - 27

SP - 3573-3586.e7

JO - Cell Reports

T2 - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 12

ER -