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

Phung, Bengt LU ; Cieśla, Maciej LU ; Sanna, Adriana LU ; Guzzi, Nicola LU ; Beneventi, Giulia LU ; Cao Thi Ngoc, Phuong LU ; Lauss, Martin LU ; Cabrita, Rita LU ; Cordero, Eugenia LU and Bosch, Ana LU , et al. (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.

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Cell Reports
volume
27
issue
12
pages
7 - 3586
publisher
Cell Press
external identifiers
  • scopus:85067127117
ISSN
2211-1247
DOI
10.1016/j.celrep.2019.05.069
language
English
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yes
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45ba3238-adab-4e6a-b5e3-2203dd89306a
date added to LUP
2019-06-25 13:37:45
date last changed
2019-07-16 04:12:31
@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},
  volume       = {27},
  year         = {2019},
}