The nucleolar-related protein Dyskerin pseudouridine synthase 1 (DKC1) predicts poor prognosis in breast cancer

Elsharawy, Khloud A.; Mohammed, Omar J.; Aleskandarany, Mohammed A.; Hyder, Ayman; El-Gammal, Hekmat; Abou‐Dobara, M. I.; Green, Andrew; Dalton, Leslie W.; Rakha, Emad A.

doi:10.1038/s41416-020-01045-7

Cited by 40 publications

(37 citation statements)

References 57 publications

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“…For example, in contrast to our results on ECs, reports on prostate, hepatocellular carcinoma, and colorectal cancers showed that high DKC1 is commonly associated with an extensive tumour growth pattern [ 25 , 34 , 35 ]. Recently, Elsharawy et al showed that high DKC1 mRNA or protein levels in breast cancer associated with poor patient outcome and unfavourable clinicopathological characteristics [ 26 ]. In a recent study in breast cancer, DKC1 over-expression associated with unfavourable clinicopathological characteristics and poor outcome [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Elsharawy et al showed that high DKC1 mRNA or protein levels in breast cancer associated with poor patient outcome and unfavourable clinicopathological characteristics [ 26 ]. In a recent study in breast cancer, DKC1 over-expression associated with unfavourable clinicopathological characteristics and poor outcome [ 26 ]. Two publicly available “Breast Cancer Gene-Expression Miner v4.3” [ 26 ] and TCGA breast cancer datasets revealed high DKC1 mRNA levels to significantly correlate with larger tumour size, higher tumour grades, and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study in breast cancer, DKC1 over-expression associated with unfavourable clinicopathological characteristics and poor outcome [ 26 ]. Two publicly available “Breast Cancer Gene-Expression Miner v4.3” [ 26 ] and TCGA breast cancer datasets revealed high DKC1 mRNA levels to significantly correlate with larger tumour size, higher tumour grades, and poor prognosis. At the protein level, high dyskerin protein levels, whether in the nucleus and/or nucleoli, were reported to be associated with aggressive features in breast cancer [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Two publicly available “Breast Cancer Gene-Expression Miner v4.3” [ 26 ] and TCGA breast cancer datasets revealed high DKC1 mRNA levels to significantly correlate with larger tumour size, higher tumour grades, and poor prognosis. At the protein level, high dyskerin protein levels, whether in the nucleus and/or nucleoli, were reported to be associated with aggressive features in breast cancer [ 26 ]. In those tissues, however, carcinogenesis is associated with reactivation of TA compared with healthy tissues [ 36 ], whereas high TA is a feature of healthy PP endometrium [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Available evidence suggests either the gain or loss of dyskerin to be carcinogenic [ 23 , 24 ]. High dyskerin levels have been reported in breast and prostate cancers [ 21 , 25 , 26 ] while decreased levels of dyskerin had been linked to carcinogenesis in the pituitary gland [ 27 ]. Low dyskerin levels observed in dyskeratosis congenita (DC) [ 28 ] have also been associated with an increased cancer-susceptibility before the age of 30 due to prematurely shortened telomers [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

Alnafakh

Saretzki

Midgley

et al. 2021

Cancers

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Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. We aimed to examine the expression, prognostic relevance, and functional role of dyskerin in human EC. Endometrial samples from a cohort of 175 women were examined with immunohistochemistry, immunoblotting, and qPCR. The EC cells were transfected with Myc-DDK-DKC1 plasmid and the effect of dyskerin overexpression on EC cell proliferation was assessed by flow cytometry. Human endometrium expresses dyskerin (DKC1) and dyskerin protein levels are significantly reduced in ECs when compared with healthy postmenopausal endometrium. Low dyskerin immunoscores were potentially associated with worse outcomes, suggesting a possible prognostic relevance. Cancer Genome Atlas (TCGA) ECs dataset (n = 589) was also interrogated. The TCGA dataset further confirmed changes in DKC1 expression in EC with prognostic significance. Transient dyskerin overexpression had a negative effect on EC cell proliferation. Our data demonstrates a role for dyskerin in normal endometrium for the first time and confirms aberrant expression with possible prognostic relevance in EC. Interventions aimed at modulating dyskerin levels may provide novel therapeutic options in EC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

Alnafakh

Saretzki

Midgley

et al. 2021

Cancers

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5‐Fluorouracil treatment represses pseudouridine‐containing miRNA export into extracellular vesicles

Qu,

Nelson,

Liu

et al. 2024

J of Extracellular Bio

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Abstract5‐Fluorouracil (5‐FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5‐FU is also incorporated into RNA causing defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. We examined the impact of 5‐FU on post‐transcriptional small RNA modifications (PTxMs) and the expression and export of RNA into small extracellular vesicles (sEVs). EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell‐cell communication. We found that treatment of colorectal cancer (CRC) cells with 5‐FU represses sEV export of miRNA and snRNA‐derived RNAs, but promotes export of snoRNA‐derived RNAs. Strikingly, 5‐FU treatment significantly decreased the levels of pseudouridine on both cellular and sEV small RNA profiles. In contrast, 5‐FU exposure led to increased levels of cellular small RNAs containing a variety of methyl‐modified bases. These unexpected findings show that 5‐FU exposure leads to altered RNA expression, base modification, and aberrant trafficking and localization of small RNAs.

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Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma

Zhang,

Zhu,

Huang

et al. 2024

J Cancer Res Clin Oncol

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Background Esophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer. Methods Clinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments. Results In this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis. Conclusion In this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.

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The nucleolar-related protein Dyskerin pseudouridine synthase 1 (DKC1) predicts poor prognosis in breast cancer

Cited by 40 publications

References 57 publications

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

5‐Fluorouracil treatment represses pseudouridine‐containing miRNA export into extracellular vesicles

Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma

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