The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
(2019) In Cell Reports 27(12). p.7-3586- 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... (More)
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.
(Less)
- author
- organization
-
- Melanoma Genomics (research group)
- 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 (research group)
- Experimental oncology (research group)
- Molecular therapeutics in breast cancer (research group)
- Breastcancer-genetics
- Lund Melanoma Study Group (research group)
- EpiHealth: Epidemiology for Health
- Surgery (Lund)
- publishing date
- 2019-06-18
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Reports
- volume
- 27
- issue
- 12
- pages
- 7 - 3586
- publisher
- Cell Press
- external identifiers
-
- pmid:31216476
- scopus:85067127117
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2019.05.069
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
- id
- 45ba3238-adab-4e6a-b5e3-2203dd89306a
- date added to LUP
- 2019-06-25 13:37:45
- date last changed
- 2024-11-13 10:46:03
@article{45ba3238-adab-4e6a-b5e3-2203dd89306a, abstract = {{<p>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.</p>}}, author = {{Phung, Bengt and Cieśla, Maciej and Sanna, Adriana and Guzzi, Nicola and Beneventi, Giulia and Cao Thi Ngoc, Phuong and Lauss, Martin and Cabrita, Rita and Cordero, Eugenia and Bosch, Ana and Rosengren, Frida and Häkkinen, Jari and Griewank, Klaus and Paschen, Annette and Harbst, Katja and Olsson, Håkan and Ingvar, Christian and Carneiro, Ana and Tsao, Hensin and Schadendorf, Dirk and Pietras, Kristian and Bellodi, Cristian and Jönsson, Göran}}, issn = {{2211-1247}}, language = {{eng}}, month = {{06}}, number = {{12}}, pages = {{7--3586}}, publisher = {{Cell Press}}, series = {{Cell Reports}}, title = {{The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma}}, url = {{http://dx.doi.org/10.1016/j.celrep.2019.05.069}}, doi = {{10.1016/j.celrep.2019.05.069}}, volume = {{27}}, year = {{2019}}, }