The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
Authors: Eugenia Cordero
Ana Bosch
Katja Harbst
H√•kan Olsson
Christian Ingvar
Hensin Tsao
Annette Paschen
Jari H√§kkinen
Rita Cabrita
Bengt Phung
Cristian Bellodi
Martin Lauss
Giulia Beneventi
Adriana Sanna
G√∂ran J√∂nsson
Phuong Cao Thi Ngoc
Ana Carneiro
Dirk Schadendorf
Maciej Cie≈õla
Frida Rosengren
Nicola Guzzi
Klaus Griewank
Kristian Pietras
Journal: Cell Reports (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: DDX3X; IRES; MITF; melanocyte; melanoma
Affiliations: Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden., Department of Laboratory Medicine, Lund University, Lund, Sweden., Department of Dermatology, University Hospital of Essen, Essen, Germany., Department of Surgery, Sk√•ne University Hospital, Lund, Sweden., Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Oncology and Hematology, Sk√•ne University Hospital, Lund, Sweden., Department of Dermatology, Harvard Medical School, Boston, MA, USA., Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden. Electronic address: ., Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden. Electronic address: .

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 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. 

Retracted: No

PubPeer comments:
  Authors declare no conflict of interests with regards to the submitted work.  We are indebted to Param Shradhey Swami Ramdev Ji for his financial and institutional supports to accomplish this research work Perhaps the authors have a non-standard understanding of the concept of  conflict of interests . The authors are all linked to the  Patanjali Research Institute or  Department of Allied and Applied Sciences, University of Patanjali . Indeed, the first author is partner with Swami Ramdev in the Patanjali business empire, and Vice-Chancellor of the University of Patanjali ( University of Patanjali (UOP) is a manifestation of the holy vision of His Holiness Swami Ramdev ji and Revered Acharya Balkrishna ji ). The subject of the study, Divya-Swasari-Ras (DSR) is described as  a calcium containing herbal formulation that has been prescribed in India by ayurvedic practitioners, as a remedy for common cold, chronic cough, asthma and phlegm accumulation in chest , and later as a  traditional calcio-herbal formulation . The implication is that it is time-honoured and traditional. Nothing is said about the source of the material for the study. In fact DSR appears to be a proprietary product, first formulated by Swami Ramdev and distributed exclusively by the Patanjali business group, employer of the authors (other than Balkrishna). They are employed to deliver evidence that it works. ,