DEAD box RNA helicases crucial regulators of gene expression and oncogenesis

Sarkar, Moumita; Ghosh, Mrinal K.

doi:10.2741/4386

Cited by 40 publications

(14 citation statements)

References 160 publications

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“…DDX43 has published ATP-dependent RNA helicase activity (Talwar et al, 2017), whereas DDX53 has not been biochemically characterized to date. Similar to DDX5 and DDX17, DDX43 and DDX53 are linked to cancers (Sarkar & Ghosh, 2016). To permit genetic analysis of DDX5 function, Iggo et al cloned yeast genes related to DDX5 and named them dbp2 in Schizosaccharomyces pombe and DBP2 in Saccharomyces cerevisiae ( S. cerevisiae ), for DEAD-box protein 2 (Iggo et al, 1991).…”

Section: The History and Sequence Analysis Of The Ddx5/dbp2 Subfamilymentioning

confidence: 99%

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

2018

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The mammalian DEAD-box RNA helicase DDX5, its paralog DDX17, and their orthologs in Saccharomyces cerevisiae and Drosophila melanogaster, namely Dbp2 and Rm62, define a subfamily of DEAD-box proteins. Members from this subfamily share highly conserved protein sequences and cellular functions. They are involved in multiple steps of RNA metabolism including mRNA processing, microRNA processing, ribosome biogenesis, RNA decay, and regulation of long non-coding RNA activities. The DDX5/Dbp2 subfamily is also implicated in transcription regulation, cellular signalling pathways, and energy metabolism. One emerging theme underlying the diverse cellular functions is that the DDX5/Dbp2 subfamily of DEAD-box helicases act as chaperones for complexes formed by RNA molecules and proteins (RNP) in vivo. This RNP chaperone activity governs the functions of various RNA species through their life time. Importantly, mammalian DDX5 and DDX17 are involved in cancer progression when overexpressed through alteration of transcription and signalling pathways, meaning that they are possible targets for cancer therapy.

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Section: The History and Sequence Analysis Of The Ddx5/dbp2 Subfamilymentioning

confidence: 99%

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

2018

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“…Mounting evidences suggest p68 to play a crucial role in cancer development and progression. It is reported to be overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors like β-catenin, NF-κB p50, MAML1 and Androgen Receptor [1–4].…”

Section: Introductionmentioning

confidence: 99%

RNA helicase p68 deploys β-catenin in regulating RelA/p65 gene expression: implications in colon cancer

Khare

Tabassum

Chatterjee³

et al. 2019

J Exp Clin Cancer Res

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Background RelA/p65 a crucial member of NF-κB signaling pathway plays diverse role in mediating oncogenesis. Limited knowledge prevails on the mechanistic insights of RelA gene regulation. RNA helicase p68 apart from being a vital player of RNA metabolism acts as a transcriptional coactivator of several oncogenic transcription factors including β-catenin and is highly implicated in cancer progression. In this study, we aim to discern the molecular mechanism of how an RNA helicase, p68 deploys a major oncogenic signaling pathway, Wnt/ β-catenin to regulate the expression of RelA, an indispensable component of NF-κB signaling pathway towards driving colon carcinogenesis. Methods Immunoblotting and quantitative RT-PCR was performed for determining the protein and mRNA expressions of the concerned genes respectively. Luciferase assay was employed for studying the promoter activity of RelA. Chromatin immunoprecipitation was used to evaluate the occupancy of transcription factors on the RelA promoter. Immunohistochemical analysis was conducted using FFPE sections derived from normal human colon and colon cancer patient samples. Finally, a syngeneic colorectal allograft mouse model was used to assess physiological significance of the in vitro findings. Results p68, β-catenin and RelA proteins were found to bear strong positive correlation in normal and colon carcinoma patient samples. Both p68 and β-catenin increased RelA mRNA and protein expression. p68, β-catenin and Wnt3a elevated RelA promoter activity. Conversely, p68 and β-catenin knockdown diminished RelA promoter activity and led to reduced RelA mRNA and protein expression. p68 was perceived to occupy RelA promoter with β-catenin at the TCF4/LEF (TBE) sites thereby potentiating RelA transcription. p68 and β-catenin alliance positively modulated the expression of signature NF-κB target genes. Enhanced NF-κB target gene expression by p68 was corroborated by findings in clinical samples. Tumors generated in mice colorectal allograft model, stably expressing p68 further reinforced our in vitro findings. Conclusions We report for the first time a novel mechanism of alliance between p68 and β-catenin in regulating the expression of RelA and stimulating the NF-κB signaling axis towards driving colon carcinogenesis. This study unravels novel modes of p68-mediated colon carcinogenesis, marking it a potential target for therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1304-y) contains supplementary material, which is available to authorized users.

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“…The cellular superfamily of RNA helicases, also known as DExD/H-box helicases, are involved in every aspect of RNA metabolism 15 , 16 . However, in recent years, their involvement has been identified in an increasing number of other cellular functions such as: innate immune responses against pathogens, oncogenesis, and inflammatory diseases 17 , 18 .…”

Section: Introductionmentioning

confidence: 99%

Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells

Rahman

Bagdassarian

Ali

et al. 2017

Sci Rep

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Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic virotherapeutic for the treatment of a variety of human cancers. MYXV tropism for human cancer cells is largely mediated by intracellular signaling networks that regulate viral replication or innate antiviral response pathways. Thus, MYXV is fully or partially permissive for the majority of human cancer cells that harbor defects in antiviral signaling, but a minority are nonpermissive because the virus infection aborts before its completion. To identify host factors relevant for MYXV tropism in human cancer cells, we performed a small interfering RNA (siRNA) library screen targeting the 58 human DEAD-box RNA helicases in two permissive human cancer cells (HeLa and A549), one semi-permissive (786-0), and one nonpermissive cell line (PANC-1). Five host RNA helicases (DDX3X, DDX5, DHX9, DHX37, DDX52) were inhibitory for optimal replication and thus classified as anti-viral, while three other cellular RNA helicases (DHX29, DHX35, RIG-I) were identified as pro-viral or pro-cellular because knockdown consistently reduced MYXV replication and/or required metabolic functions of permissive cancer cells. These findings suggest that replication of MYXV, and likely all poxviruses, is dramatically regulated positively and negatively by multiple host DEAD-box RNA helicases.

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DEAD box RNA helicases crucial regulators of gene expression and oncogenesis

Cited by 40 publications

References 160 publications

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

RNA helicase p68 deploys β-catenin in regulating RelA/p65 gene expression: implications in colon cancer

Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells

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