The eIF4E2‐Directed Hypoxic Cap‐Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment

Melanson, Gaelan; Timpano, Sara; Uniacke, James

doi:10.1155/2017/6098107

Cited by 25 publications

(27 citation statements)

References 106 publications

(170 reference statements)

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“…3F). Mechanisms by which HIF-2␣ acted at the 3= UTRs of the rHREs of select mRNAs along with RBM4 to mediate joining of the 5= end and eIF4E2 were initially proposed (16,22,47). It is important to note that cap-binding assays are performed with m 7 GTP bound to agarose beads and not to an mRNA (48).…”

Section: Discussionmentioning

confidence: 99%

DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation

Evagelou

Bebenek

Specker

et al. 2020

Molecular and Cellular Biology

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Hypoxia is a deficiency in oxygen delivery to tissues and is connected to physiological and pathophysiological processes such as embryonic development and cancer. The master regulators of oxygen homeostasis in mammalian cells are the heterodimeric hypoxia-inducible transcription factors 1 and 2 (HIF-1 and HIF-2, respectively). The oxygen-labile HIF-2α subunit has been implicated not only in transcription but also as a regulator of eukaryotic initiation factor 4E2 (eIF4E2)-directed hypoxic translation. Here, we have identified the DEAD box protein family member DDX28 as an interactor and negative regulator of HIF-2α that suppresses HIF-2α’s ability to activate eIF4E2-directed translation. Stable silencing of DDX28 via short hairpin RNA (shRNA) in hypoxic human U87MG glioblastoma cells caused an increase of eIF4E2 binding to the m7GTP cap structure and the translation of eIF4E2 target mRNAs (including the HIF-2α mRNA itself). DDX28 depletion elevated nuclear and cytoplasmic HIF-2α protein, but HIF-2α transcriptional activity did not increase, possibly due to its already high nuclear abundance in hypoxic control cells. Depletion of DDX28 conferred a proliferative advantage to hypoxic, but not normoxic, cells. DDX28 protein levels are reduced in several cancers, including gliomas, relative to levels in normal tissue. Therefore, we uncover a regulatory mechanism for this potential tumor suppressor in the repression of HIF-2α- and eIF4E2-mediated translation activation of oncogenic mRNAs.

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Section: Discussionmentioning

confidence: 99%

DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation

Evagelou

Bebenek

Specker

et al. 2020

Molecular and Cellular Biology

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“…Many studies have reported the role of cap-dependent protein translation in oncogenesis, and translation initiation factors have long been recognized as potential sources of dysregulation during the oncogenic process. [19][20][21] However, the role of nuclear cap-binding protein 1 in the development and progression of cancer is not well F I G U R E 6 NCBP1 together with NCBP3 regulates CUL4B mRNA expression. A, RNA immunoprecipitation assay.…”

Section: Discussionmentioning

confidence: 99%

NCBP1 promotes the development of lung adenocarcinoma through up‐regulation of CUL4B

Zhang

Wang

Tan

et al. 2019

J Cellular Molecular Medi

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Lung cancer is the most frequent cancer type and is the leading cause of tumour‐associated deaths worldwide. Nuclear cap‐binding protein 1 (NCBP1) is necessary for capped RNA processing and intracellular localization. It has been reported that silencing of NCBP1 resulted in cell growth reduction in HeLa cells. Nevertheless, its clinical significance and underlying molecular mechanisms in non–small‐cell lung cancer remain unclear. In this study, we found that NCBP1 was significantly overexpressed in lung cancer tissues and several lung cancer cell lines. Through knockdown and overexpression experiments, we showed that NCBP1 promoted lung cancer cell growth, wound healing ability, migration and epithelial‐mesenchymal transition. Mechanistically, we found that cullin 4B (CUL4B) was a downstream target gene of NCBP1 in NSCLC. NCBP1 up‐regulated CUL4B expression via interaction with nuclear cap‐binding protein 3 (NCBP3). CUL4B silencing significantly reversed NCBP1‐induced tumorigenesis in vitro. Based on these findings, we propose a model involving the NCBP1‐NCBP3‐CUL4B oncoprotein axis, providing novel insight into how CUL4B is activated and contributes to LUAD progression.

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“…Alternatively, other studies suggest chronically hypoxic cancer cells are able to take advantage of a non-canonical cap-dependent pathway, which is both HIF-2α dependent and distinct from mTORC1 suppression, thus maintaining de-novo protein synthesis and tumour growth under chronic hypoxia. 55,56 There are currently no direct links to PCa 57 and general therapeutic approaches are at an early stage, 56 but progress in this field should be followed closely.…”

Section: The Biochemistry Of Hypoxia: Implications For Prostate Cancermentioning

confidence: 99%

Bad neighbours: hypoxia and genomic instability in prostate cancer

Ashton

Bristow

2020

BJR

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Prostate cancer (PCa) is a clinically heterogeneous disease and has poor patient outcome when tumours progress to castration-resistant and metastatic states. Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in localised PCa patients. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal evolution due to an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a “contextual lethal“ vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to PCa, and also characterise the role of hypoxia in driving early metastatic spread. On this basis, PCa patients with hypoxic tumours can be better stratified into risk categories and treated with appropriate therapies to prevent progression.

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The eIF4E2‐Directed Hypoxic Cap‐Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment

Cited by 25 publications

References 106 publications

DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation

DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation

NCBP1 promotes the development of lung adenocarcinoma through up‐regulation of CUL4B

Bad neighbours: hypoxia and genomic instability in prostate cancer

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