A Forward Genetic Screen Identifies Eukaryotic Translation Initiation Factor 3, Subunit H (eIF3h), as an Enhancer of Variegation in the Mouse

Daxinger, Lucia; Oey, Harald; Apedaile, Anwyn; Sutton, Joanne; Ashe, Alyson; Whitelaw, Emma

doi:10.1534/g3.112.004036

Cited by 17 publications

(9 citation statements)

References 20 publications

(23 reference statements)

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“…Over the past decade, the contribution of EIF3 to malignant transformation and progression has been established, and a previous study demonstrated that EIF3H expression was up-regulated in 18% of breast cancers and 30% of prostate cancers ( 10 ). Earlier studies also indicated that EIF3H was essential for maintaining the malignant state in cells ( 11 ). Zhu et al ( 12 ) reported that knockdown of EIF3H expression in hepatocellular carcinoma cells promoted apoptosis, and inhibited cell growth, colony formation, migration, as well as tumour growth in nude mice.…”

Section: Discussionmentioning

confidence: 90%

Eukaryotic translation initiation factor 3H suppression inhibits osteocarcinoma cell growth and tumorigenesis

et al. 2018

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Eukaryotic translation initiation factor 3H subunit (EIF3H) is a member of the EIF3 family and exhibits a central role in translation initiation in higher eukaryotes. Although EIF3H expression is upregulated in numerous tumour types, its potential role in human osteosarcoma (OS) has not yet been investigated. In the present study, it was demonstrated that EIF3H mRNA expression was upregulated in the human OS cell lines Saos-2 and U2OS. A recombinant lentivirus harbouring short hairpin RNA targeting EIF3H was constructed and successfully infected human OS Saos-2 and U2OS cells, resulting in 95% downregulated EIF3H expression compared with the respective control groups. Knockdown of EIF3H significantly inhibited the proliferation and colony formation of OS cells in vitro, and tumour growth in nude mice in vivo. Flow cytometry analysis revealed cell cycle arrest and promotion of apoptosis in OS cells with EIF3H knocked down. In conclusion, the results strongly suggested that EIF3H is a critical factor mediating the growth of OS cells and may represent a novel therapeutic target.

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Section: Discussionmentioning

confidence: 90%

Eukaryotic translation initiation factor 3H suppression inhibits osteocarcinoma cell growth and tumorigenesis

et al. 2018

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“…The identities of many of the underlying mutations have been recently reported and, not surprisingly, many occur in genes with known functions in DNA methylation and chromatin modification (4,13,14,36,37). The screen revealed both enhancers and suppressors of epigenetic variegation, including DNMTs (Dnmt1 and Dnmt3b), HMTs (Setdb1, Suv39h1), a histone deacetylase (Hdac1), components of chromatin remodeling machines (Smarca4/BRG1, Smarca5, Smarcc1/BAF155, Pbrm1/BAF180, and Hdac1), epigenetic regulators (Smchd1, Uhrf1, Trim28/KAP1/TIF1b, and WIZ), telomeric proteins (Rif1, Smchd1), chromatin-dependent transcriptional regulators (Brd1, Rlf, and Baz1b), and the translation initiation factor eIF3h.…”

Section: Figmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

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“…Intriguing data showing that eIF3h modulates epigenetic changes would suggest that, at least partially, these changes may be mRNA-specific and result in reprogramming of cells. 122 Another remarkable case is eIF4G1. eIF4G1 is an essential part of the eIF4F complex, where it acts by stimulating cap-dependent translation.…”

Section: The Case For Rapamycin-insensitive Translationmentioning

confidence: 99%

Translation factors and ribosomal proteins control tumor onset and progression: how?

2013

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Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus.

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A Forward Genetic Screen Identifies Eukaryotic Translation Initiation Factor 3, Subunit H (eIF3h), as an Enhancer of Variegation in the Mouse

Cited by 17 publications

References 20 publications

Eukaryotic translation initiation factor 3H suppression inhibits osteocarcinoma cell growth and tumorigenesis

Eukaryotic translation initiation factor 3H suppression inhibits osteocarcinoma cell growth and tumorigenesis

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Translation factors and ribosomal proteins control tumor onset and progression: how?

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