The Role of DND1 in Cancers

Zhang, Yun; Godavarthi, Jyotsna D; Williams-Villalobo, Abie; Polk, Shahrazad; Matin, Angabin

doi:10.3390/cancers13153679

Cited by 6 publications

(5 citation statements)

References 60 publications

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“…Furthermore, we examined the potential molecular impact of DND1 on malignant somatic cells. Since DND1 regulates translation via increasing or decreasing target mRNA stability [ 1 ], we queried genes that are co-expressed with DND1 in 14 somatic cancer types: breast invasive carcinoma (BIC), bladder urothelial carcinoma (BUC), colorectal adenocarcinoma (CA), glioblastoma multiforme (GBM), liver hepatocellular carcinoma (HCC), lung adenocarcinoma (LA), lung squamous cell carcinoma (LSCC), ovarian serous cystadenocarcinoma (OSC), pancreatic adenocarcinoma (PanA), prostate adenocarcinoma (ProA), kidney renal clear cell carcinoma (RCCC), kidney renal papillary cell carcinoma (RPCC), stomach adenocarcinoma (SA), and skin cutaneous melanoma (SCM). In addition, as DND1 plays an important role in TGCT formation in 129 mouse strain [ 10 , 15 ], we also queried its co-expressed genes in human TGCT.…”

Section: Resultsmentioning

confidence: 99%

“…Since DND1 can function in translational regulation by either stabilizing or degrading mRNA [ 1 ], identification of a large number of genes that significantly co-express with DND1 in human cancers ( Fig. 3 ) is expected.…”

Section: Discussionmentioning

confidence: 99%

“…The Dead-End 1 (DND1) is an RNA-binding protein containing two RNA recognition motifs (RRMs) in tandem, followed by a double-stranded RNA-binding motif at the carboxyl-terminus [ 1 ]. DND1 is a multifunctional protein and has been found to exhibit diverse molecular activities.…”

Section: Introductionmentioning

confidence: 99%

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In silico analysis of DND1 and its co-expressed genes in human cancers

Zhang

Chachad

et al. 2022

Biochemistry and Biophysics Reports

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Dead-End (DND1) is an RNA-binding protein involved in translational regulation. Defects in DND1 gene causes germ cell tumors and sterility in rodents. Experimental studies with human somatic cancer cells indicate that DND1 has anti-proliferative and pro-apoptotic function in some while oncogenic function in other cells. We examined The Cancer Genome Atlas data for gene alterations and gene expression changes in DND1 in a variety of human cancers. We found that DND1 is amplified, deleted or mutated in multiple human cancers. In different cancers, DND1 alteration correlates with increased diagnosis age of patients, shift in tumor spectrum or change of tumor sites and in some cases is significantly associated with worse survival for cancer patients. For 15 cancers, we retrieved expression data of thousands of genes that co-expressed with DND1 . We found that these cancers contain different percentage of genes that are positively or negatively co-expressed with DND1 . Ingenuity Pathway Analysis was performed to explore the biological implications of these genes. More than 10 canonical pathways were identified and each cancer type exhibits unique pathway profiles. Comparison analysis across all 15 cancer types showed that some cancers exhibit strikingly similar profiles of DND1-correlated signaling pathway activation or suppression. Our data reinforce the notion that the biological role of DND1 is cell-type specific and suggest that DND1 may play opposing role by exerting anti-proliferative effects in some cancer cells while being pro-proliferative in others. Our study provides valuable insights to direct experimental investigations of DND1 function in somatic cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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In silico analysis of DND1 and its co-expressed genes in human cancers

Zhang

Chachad

et al. 2022

Biochemistry and Biophysics Reports

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“…In 2005, the Ter mutation was mapped to a point mutation that introduced a premature STOP codon in the gene Dnd1 ( Dnd1 Ter ) ( Youngren et al, 2005 ; Zhang et al, 2021 ). Dnd1 encodes an RNA-binding protein for which several functions have been described, and multiple RNA targets have been identified ( Yamaji et al, 2017 ; Ruthig et al, 2019 ; Ruthig et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Oxygen availability influences the incidence of testicular teratoma in Dnd1Ter/+ mice

Bustamante-Marin

Capel

2023

Front. Genet.

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Testicular teratomas and teratocarcinomas are the most common testicular germ cell tumors in early childhood and young men, and they are frequently found unilaterally in the left testis. In 129/SvJ mice carrying a heterozygous copy of the potent modifier of tumor incidence Ter, a point mutation in the dead-end homolog one gene (Dnd1Ter/+), ∼70% of the unilateral teratomas arise in the left testis. We previously showed that in mice, left/right differences in vascular architecture are associated with reduced hemoglobin saturation and increased levels of the hypoxia inducible factor-1 alpha (HIF-1α) in the left compared to the right testis. To test the hypothesis that systemic reduction of oxygen availability in Dnd1Ter/+ mice would lead to an increased incidence of bilateral tumors, we placed pregnant females from 129/SvJ Dnd1Ter/+ intercross matings in a hypobaric chamber for 12-h intervals. Our results show that in 129/SvJ Dnd1Ter/+ male gonads, the incidence of bilateral teratoma increased from 3.3% to 64% when fetuses were exposed to acute low oxygen conditions for 12-h between E13.8 and E14.3. The increase in tumor incidence correlated with the maintenance of high expression of pluripotency genes Oct4, Sox2 and Nanog, elevated activity of the Nodal signaling pathway, and suppression of germ cell mitotic arrest. We propose that the combination of heterozygosity for the Ter mutation and hypoxia causes a delay in male germ cell differentiation that promotes teratoma initiation.

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“…musashi RNA-binding protein 2) e METTL3 (do inglês, methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit). A proteína DND1 é uma RBP que promove a estabilidade de seus transcritos-alvo ao ocultar sítios reconhecidos por miRNAs que, por sua vez, desestabilizam o transcrito, promovendo sua degradação (Zhang et al, 2021). A região 3' UTR de TSC1 também apresenta motivos em potencial para DND1, sendo a proteína uma interessante candidata a sua regulação.…”

Section: Discussionunclassified

Regulação da expressão dos genes TSC1 e TSC2 na via de mTORC1

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Introduction: Tuberous sclerosis complex (TSC) is a multisystemic disease characterized by benign tumors in various organs and caused by pathogenic variants in the tumor suppressor genes TSC1 or TSC2. The TSC1 and TSC2 proteins inhibit the mTORC1 pathway, which is central to the control of cell growth and proliferation. mTORC1 activity has been linked to the differential expression of specific genes. However, it is unknown whether the pathway's activity has any effect on the mRNA and protein levels expressed by the TSC complex (TSC1, TSC2, and TBC1D7). The unkempt protein (UNK), encoded by the UNK gene, is an RNA-binding protein that regulates mRNA expression in neuronal differentiation processes, serving as a constituent of mTORC1. Previous results from our lab identified co-expression of TSC1 and UNK mRNA in tumors without pathogenic alterations in TSC1 and TSC2. There is limited information on the regulation of TSC1 and TSC2 gene expression in modulating mTORC1 pathway activity. Moreover, it is unclear whether UNK regulates mRNA expression of certain genes in this pathway. Aims: The specific aims of this study were to assess (i) the effect(s) of the mTOR pathway on the RNA and protein levels expressed by TSC1, TSC2, TBC1D7, and UNK genes; and (ii) whether shRNA-mediated silencing of UNK alters the protein levels of TSC1 and TSC2 in HEK293T cells. Methods: Differential gene expression analyses were performed on publicly available transcriptome data obtained from HEK293T cells treated with rapamycin, SH-SY5Y cell line submitted to UNK knocking-down, or soleus muscle from mice that had been treated with rapamycin or caloric restriction for 15 months. In the laboratory, HEK293T cells were treated with rapamycin for 24 hours. A cell line was established by transduction of lentiviral particles modified to express short-hairpin RNA (shRNA) targeting UNK. Western blotting was conducted for quantitative comparison of target proteins. Results: HEK293T cells subjected to mTORC1 pathway repression by rapamycin treatment for 72 hours had an increase in TSC2 mRNA levels. Transcriptome analysis of soleus muscle from mice treated in vivo with rapamycin for 15 months revealed an increase in Tsc2 mRNA and a reduction in Tsc1 and Tbc1d7 mRNA. UNK knock-down in human SH-SY5Y cells resulted in a reduction in TSC2 mRNA. Analysis of the TSC1-TSC2-TBC1D7 complex proteins in unmodified HEK293T cells showed an increase in UNK levels 24 hours after starvation, which was maintained during consecutive rapamycin treatment for an additional 24 hours. A HEK293T cell line with significant reduction of UNK protein was generated, and no change was observed in the levels of any of the three TSC1-TSC2-TBC1D7 complex proteins. Conclusions: Our data indicate that the mTORC1 pathway has a negative effect on TSC2 mRNA levels in HEK293T cells and mouse soleus muscle. In HEK293T cells, mTORC1 pathway inactivity increases UNK protein levels. Reduction of UNK protein in this cell line does not alter the levels of the TSC1-TSC2-TBC1D7 complex proteins. In...

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The Role of DND1 in Cancers

Cited by 6 publications

References 60 publications

In silico analysis of DND1 and its co-expressed genes in human cancers

In silico analysis of DND1 and its co-expressed genes in human cancers

Oxygen availability influences the incidence of testicular teratoma in Dnd1Ter/+ mice

Regulação da expressão dos genes TSC1 e TSC2 na via de mTORC1

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