DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Xu, Kun; Sun, Shenghui; Yan, Mingjing; Cui, Ju; Yang, Yue; Li, Wenlin; Huang, Xiuqing; Dou, Lin; Chen, Beidong; Tang, Weiqing; Lv, Ming; Li, Jian; Shen, Tao

doi:10.3389/fonc.2022.943032

Cited by 23 publications

(33 citation statements)

References 157 publications

(186 reference statements)

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“…3B ). DDX5 (DEAD (Asp‐Glu‐Ala‐Asp) box polypeptide 5), also known as RNA helicase p68, is involved in a variety of cellular processes, including transcription, alternative splicing, translation and precursor messenger RNA processing [ 31 ]. In addition, DDX5 was reported to be abnormally expressed in a variety of tumours and to play a crucial role in tumour progression [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

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HNRNPU promotes the progression of triple-negative breast cancer via RNA transcription and alternative splicing mechanisms

Han

Liu

et al. 2022

Cell Death Dis

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Triple-negative breast cancer (TNBC) is a great detriment to women’s health due to the lack of effective therapeutic targets. In this study, we employed an integrated genetic screen to identify a pivotal oncogenic factor, heterogeneous nuclear ribonucleoprotein U (HNRNPU), which is required for the progression of TNBC. We elucidated the pro-oncogenic role of HNRNPU, which can induce the proliferation and migration of TNBC cells via its association with DEAD box helicase 5 (DDX5) protein. Elevated levels of the HNRNPU-DDX5 complex prohibited the intron retention of minichromosome maintenance protein 10 (MCM10) pre-mRNA, decreased nonsense-mediated mRNA decay, and activated Wnt/β-catenin signalling; on the other hand, HNRNPU-DDX5 is located in the transcriptional start sites (TSS) of LIM domain only protein 4 (LMO4) and its upregulation promoted the transcription of LMO4, consequently activating PI3K-Akt-mTOR signalling. Our data highlight the synergetic effects of HNRNPU in RNA transcription and splicing in regulating cancer progression and suggest that HNRNPU may act as a potential molecular target in the treatment of TNBC.

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Section: Resultsmentioning

confidence: 99%

“…including transcription, alternative splicing, translation and precursor messenger RNA processing [31]. In addition, DDX5 was reported to be abnormally expressed in a variety of tumours and to play a crucial role in tumour progression [32].…”

Section: Hnrnpu Binds To Ddx5 To Form a Complex To Exert Tumorigenic ...mentioning

confidence: 99%

HNRNPU promotes the progression of triple-negative breast cancer via RNA transcription and alternative splicing mechanisms

Han

Liu

et al. 2022

Cell Death Dis

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“…Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption ( Váraljai et al, 2015 ). Most likely, also the upstream regulator DDX5, interacting with TP53, directly regulates transcriptional activity of mitochondrial-related genes by binding at or near their promoter ( Xing et al, 2020 ; Xu et al, 2022 ). Similar to our results, DDX5 expression is reported to be downregulated in palmitate-stimulated hepatocytes but also in patients with NASH ( Zhang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Positive allosteric GABAA receptor modulation counteracts lipotoxicity-induced gene expression changes in hepatocytes in vitro

Rohbeck

Niersmann²,

Köhrer³

et al. 2023

Front. Physiol.

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Introduction: We have previously shown that the novel positive allosteric modulator of the GABAA receptor, HK4, exerts hepatoprotective effects against lipotoxicity-induced apoptosis, DNA damage, inflammation and ER stress in vitro. This might be mediated by downregulated phosphorylation of the transcription factors NF-κB and STAT3. The current study aimed to investigate the effect of HK4 on lipotoxicity-induced hepatocyte injury at the transcriptional level.Methods: HepG2 cells were treated with palmitate (200 μM) in the presence or absence of HK4 (10 μM) for 7 h. Total RNA was isolated and the expression profiles of mRNAs were assessed. Differentially expressed genes were identified and subjected to the DAVID database and Ingenuity Pathway Analysis software for functional and pathway analysis, all under appropriate statistical testing.Results: Transcriptomic analysis showed substantial modifications in gene expression in response to palmitate as lipotoxic stimulus with 1,457 differentially expressed genes affecting lipid metabolism, oxidative phosphorylation, apoptosis, oxidative and ER stress among others. HK4 preincubation resulted in the prevention of palmitate-induced dysregulation by restoring initial gene expression pattern of untreated hepatocytes comprising 456 genes. Out of the 456 genes, 342 genes were upregulated and 114 downregulated by HK4. Enriched pathways analysis of those genes by Ingenuity Pathway Analysis, pointed towards oxidative phosphorylation, mitochondrial dysregulation, protein ubiquitination, apoptosis, and cell cycle regulation as affected pathways. These pathways are regulated by the key upstream regulators TP53, KDM5B, DDX5, CAB39 L and SYVN1, which orchestrate the metabolic and oxidative stress responses including modulation of DNA repair and degradation of ER stress-induced misfolded proteins in the presence or absence of HK4.Discussion: We conclude that HK4 specifically targets mitochondrial respiration, protein ubiquitination, apoptosis and cell cycle. This not only helps to counteract lipotoxic hepatocellular injury through modification of gene expression, but - by targeting transcription factors responsible for DNA repair, cell cycle progression and ER stress - might even prevent lipotoxic mechanisms. These findings suggest that HK4 has a great potential for the treatment of non-alcoholic fatty liver disease (NAFLD).

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“…It contributes to colon cancer through up-regulation of proto-oncogenes and down-regulation of tumor suppressors. Thus, it is a pivotal member involved in carcinogenesis and needs to be comprehensively studied to provide insights into the process of oncogenesis and tackle the menace of tumor progression 1–4 .…”

Section: Introductionmentioning

confidence: 99%

“…Thus, it is a pivotal member involved in carcinogenesis and needs to be comprehensively studied to provide insights into the process of oncogenesis and tackle the menace of tumor progression [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

The DEAD-box protein p68 and β-catenin: the crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer

Tabassum

Basu

Ghosh

2022

Preprint

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Forkhead box M1 (FOXM1), a vital member of the Forkhead box family of transcription factors, helps in mediating oncogenesis. However, limited knowledge exists regarding the mechanistic insights into the FOXM1 gene regulation. p68, an archetypal member of the DEAD-box family of RNA helicases, shows multifaceted action in cancer progression by arbitrating RNA metabolism and transcriptionally coactivating transcription factors. Here, we report a novel mechanism of alliance between p68 and the Wnt/B-catenin pathway in regulating FOXM1 gene expression and driving colon carcinogenesis. Initial bioinformatic analyses highlighted elevated expression levels of FOXM1 and p68 in colorectal cancer datasets. Immunohistochemical assays confirmed that FOXM1 showed a positive correlation with p68 and B-catenin in both normal and colon carcinoma patient samples. Overexpression of p68 and B-catenin increased the protein and mRNA expression profiles of FOXM1, and the converse correlation occurred during downregulation. Mechanistically, overexpression and knockdown of p68 and B-catenin elevated and diminished FOXM1 promoter activity respectively. Additionally, Chromatin immunoprecipitation assay demonstrated the occupancy of p68 and B-catenin at the TCF4/LEF binding element (TBE) sites on the FOXM1 promoter. Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the p68/B-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by p68 and B-catenin in colorectal cancer.

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DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Cited by 23 publications

References 157 publications

HNRNPU promotes the progression of triple-negative breast cancer via RNA transcription and alternative splicing mechanisms

HNRNPU promotes the progression of triple-negative breast cancer via RNA transcription and alternative splicing mechanisms

Positive allosteric GABAA receptor modulation counteracts lipotoxicity-induced gene expression changes in hepatocytes in vitro

The DEAD-box protein p68 and β-catenin: the crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer

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