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

Phung, Bengt; Cieśla, Maciej; Sanna, Adriana; Guzzi, Nicola; Beneventi, Giulia; Ngoc, Phuong Cao Thi; Lauss, Martin; Cabrita, Rita; Cordero, Eugenia; Bosch, Ana; Rosengren, Frida; Häkkinen, Jari; Griewank, Klaus G.; Paschen, Annette; Harbst, Katja; Olsson, Håkan; Ingvar, Christian; Carneiro, Ana; Tsao, Hensin; Schadendorf, Dirk; Pietras, Kristian; Bellodi, Cristian; Jönsson, Göran

doi:10.1016/j.celrep.2019.05.069

Cited by 61 publications

(67 citation statements)

References 65 publications

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“…In discussing the role of MITF in melanoma and melanocytes, and in particular the usefulness of MITF as a marker for specific phenotypic states, it is important to note that MITF activity will be determined by many factors, including its expression at the mRNA level, which is driven by a range of transcriptional activators and repressors and the signals that regulate them as well as microRNAs (Goding and Arnheiter 2019); its expression at the protein level, which is dictated by its translational control (Falletta et al 2017;Phung et al 2019) and protein stability (Wu et al 2000;Xu et al 2000;Ploper et al 2015); the activity of the protein, which will be affected by posttranslational modifications that determine its nuclearcytoplasmic shuttling (Ngeow et al 2018), interaction with cofactors (Sato et al 1997;Price et al 1998), or genome-wide distribution ; and the availability of DNA-binding partners and cofactors such as β-catenin (Schepsky et al 2006) or the SWI/SNF complex (de la Serna et al 2006). Although we can infer that cells lacking significant MITF mRNA expression will likely exhibit very low MITF protein expression, the expression of MITF mRNA does not necessarily imply either that the protein is expressed or that it is active.…”

Section: Mitf and Phenotype Switching In Melanomamentioning

confidence: 99%

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

2019

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An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

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Section: Mitf and Phenotype Switching In Melanomamentioning

confidence: 99%

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

2019

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“…DDX3X was weakly associated with survival in both series when examined as a dichotomous variable but strongly associated with survival in the LMC when analyzed as a continuous variable. DDX3X is an x-linked RNA helicase, which has been linked to post-translational regulation of MITF (Microphthalmia-associated Transcription Factor) expression and development of melanoma metastasis and therapy resistance [42]. It is possible that the female advantage in relation to DDX3X may result from the adverse effect of mutation or loss of DDX3X in male patients rather than effects on immune responses.…”

Section: Discussionmentioning

confidence: 99%

Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts

Emran

Nsengimana

Punnia-Moorthy

et al. 2020

Cancers

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Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.

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“…Dysregulation of DDX3X has been associated with tumorigenesis caused by loss of function (75). Furthermore, DDX3X has been identified as a mutational cancer driver in medulloblastoma, cutaneous melanoma and chronic lymphocytic leukemia by PAN-cancer analysis (76)(77)(78). However, to the best of our knowledge, the role of DDX3X in MALT lymphoma has not been elucidated and the relationship between DDX3X mutations and disease occurrence has not been clarified.…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing

Huh

Lee

et al. 2020

Oncol Lett

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Extranodal marginal zone lymphoma is a type of low-grade B-cell lymphoma that can be classified as a mucosal-associated lymphoid tissue (MALT) lymphoma. Recently, second-generation or next-generation sequencing (NGS), which allows simultaneous sequencing of hundreds to billions of DNA strands, has been a focus of attention and is rapidly being adopted in various fields. In the present study, paraffin-embedded tissue samples of gastric MALT lymphoma (n=1) and small intestine MALT lymphoma (n=4) were selected, and DNA was extracted from the tissue samples. After performing quality control, NGS was performed using HemaSCAN™, a custom panel of 426 genes, including essential blood cancer genes. NGS revealed single nucleotide variations (SNVs), short insertions and deletions (InDels) and copy number variations (CNVs). These genomic variants were reported as annotated, known or novel variants. An annotated variant, an erb-b2 receptor tyrosine kinase 2 gene amplification, was observed in one patient. Known and novel variants, including SNVs of SET binding protein 6 (SETBP6), Runt-related transcription factor 1 and Kelch-like ECH-associated protein 1 genes, InDel of the marker of proliferation Ki-67 gene, and CNVs of the zinc finger protein 703 and NOTCH1 genes, were observed in ≥2 patients. Additionally, InDels with frameshift mutations were identified in the B-cell lymphoma/leukemia 10, DEAD-box helicase 3 X-linked, forkhead box O3 and mucin 2, oligomeric mucus/gel-forming genes in one patient. Since few NGS studies have been performed on MALT lymphoma, the current results were unable to determine if the different mutations that were identified are 'actionable' (that is, potentially responsive to a targeted therapy) Further studies are required to determine the associations between genetic mutations and the development of MALT lymphoma.

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

Cited by 61 publications

References 65 publications

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts

Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing

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