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

Animals Cell Proliferation Cellular Reprogramming DEAD-box RNA Helicases / genetics 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 Mice Mice, Inbred NOD Mice, SCID Microphthalmia-Associated Transcription Factor / genetics Prognosis Protein Biosynthesis / genetics

DDX3X IRES MITF melanocyte melanoma metastasis migration resistance therapy translation control

Journal

Cell reports

ISSN: 2211-1247

Titre abrégé: Cell Rep

Pays: United States

ID NLM: 101573691

Informations de publication

Date de publication:
18 06 2019

Historique:

received: 06 01 2019

revised: 22 03 2019

accepted: 17 05 2019

entrez: 20 6 2019

pubmed: 20 6 2019

medline: 5 8 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2019.05.069 PMID: 31216476

pubmed: 31216476

pii: S2211-1247(19)30698-9

doi: 10.1016/j.celrep.2019.05.069

pii:

doi:

Substances chimiques

Internal Ribosome Entry Sites 0

MITF protein, human 0

Microphthalmia-Associated Transcription Factor 0

DDX3X protein, human EC 3.6.1.-

DEAD-box RNA Helicases EC 3.6.4.13

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

3573-3586.e7