Dyskerin Overexpression in Human Hepatocellular Carcinoma Is Associated with Advanced Clinical Stage and Poor Patient Prognosis

Liu, Bei; Zhang, Jinglei; Huang, Chen; Liu, Hui

doi:10.1371/journal.pone.0043147

Cited by 69 publications

(73 citation statements)

References 31 publications

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“…Past studies suggest that elevated dyskerin expression levels correlate with more aggressive disease (2,3,6); however, before the current investigation, there was a paucity of functional evidence supporting the significance of dyskerin expression levels in any cancer type, and no previous report of dyskerin suppression inhibiting tumor growth in vivo. The current study not only identifies DKC1 expression as a powerful independent prognostic indicator of poor clinical outcome, but also shows that high DKC1 expression has functional significance and potential as a therapeutic target in the MYC-driven malignancy neuroblastoma.…”

Section: Discussionmentioning

confidence: 65%

“…4F). Tumorigenicity was then tested by subcutaneous engraftment of BALB/c nu/nu mice with transduced SK-N-BE (2). Upon establishment of a palpable tumor, mice received dietary doxycycline to suppress DKC1 expression.…”

Section: Downregulation Of Dkc1 Inhibits the Replication And Tumorigementioning

confidence: 99%

“…Subsequent studies demonstrated high DKC1 expression in various adult cancers, with the DKC1 promoter shown to be a target of c-Myc in breast cancer (2)(3)(4). Gene expression array and proteomic studies identified DKC1 among the suite of genes upregulated in neuroblastoma in association with MYCN amplification (5-7).…”

Section: Introductionmentioning

confidence: 99%

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MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

et al. 2016

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The RNA-binding protein dyskerin, encoded by the DKC1 gene, functions as a core component of the telomerase holoenzyme as well as ribonuclear protein complexes involved in RNA processing and ribosome biogenesis. The diverse roles of dyskerin across many facets of RNA biology implicate its potential contribution to malignancy. In this study, we examined the expression and function of dyskerin in neuroblastoma. We show that DKC1 mRNA levels were elevated relative to normal cells across a panel of 15 neuroblastoma cell lines, where both N-Myc and c-Myc directly targeted the DKC1 promoter. Upregulation of MYCN was shown to dramatically increase DKC1 expression. In two independent neuroblastoma patient cohorts, high DKC1 expression correlated strongly with poor event-free and overall survival (P < 0.0001), independently of established prognostic factors. RNAi-mediated depletion of dyskerin inhibited neuroblastoma cell proliferation, including cells immortalized via the telomerase-independent ALT mechanism. Furthermore, dyskerin attenuation impaired anchorage-independent proliferation and tumor growth. Overexpression of the telomerase RNA component, hTR, demonstrated that this proliferative impairment was not a consequence of telomerase suppression. Instead, ribosomal stress, evidenced by depletion of small nucleolar RNAs and nuclear dispersal of ribosomal proteins, was the likely cause of the proliferative impairment in dyskerindepleted cells. Accordingly, dyskerin suppression caused p53-dependent G 1 cell-cycle arrest in p53 wild-type cells, and a p53-independent pathway impaired proliferation in cells with p53 dysfunction. Together, our findings highlight dyskerin as a new therapeutic target in neuroblastoma with crucial telomerase-independent functions and broader implications for the spectrum of malignancies driven by MYC family oncogenes. Cancer Res; 76(12); 3604-17. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 65%

Section: Downregulation Of Dkc1 Inhibits the Replication And Tumorigementioning

confidence: 99%

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MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

et al. 2016

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“…However, although human dyskerin was first defined as a nucleolar protein that showed strict nucleolar localization (initially localized in the nucleoplasm, followed by a sequential translocation to the nucleoli and to the coiled bodies [52]), a recent study has indicated that the human DKC1 gene encodes a new alternatively spliced mRNA (isoform 3) which can direct the synthesis of a variant form of dyskerin that has an unexpected cytoplasmic localization and lacks the C-terminal nuclear localization signal [53]. Supporting the data, expression of dyskerin has been described in both the cytoplasm and nuclei of basal or parabasal cells in cervical lesions [54], and dyskerin staining was localized mainly in the nuclei of tumor cells and partly in the cytoplasm [55]. Further research is required to learn more about the nucleolar and cytoplasmic forms of dyskerin protein.…”

Section: Dyskerin-like Proteinsmentioning

confidence: 72%

Protein universe containing a PUA RNA‐binding domain

2013

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Here, we review current knowledge about pseudouridine synthase and archaeosine transglycosylase (PUA)‐domain‐containing proteins to illustrate progress in this field. A methodological analysis of the literature about the topic was carried out, together with a ‘qualitative comparative analysis’ to give a more comprehensive review. Bioinformatics methods for whole‐protein or protein‐domain identification are commonly based on pairwise protein sequence comparisons; we added comparison of structures to detect the whole universe of proteins containing the PUA domain. We present an update of proteins having this domain, focusing on the specific proteins present in Homo sapiens (dyskerin, MCT1, Nip7, eIF2D and Nsun6), and explore the existence of these in other species. We also analyze the phylogenetic distribution of the PUA domain in different species and proteins. Finally, we performed a structural comparison of the PUA domain through data mining of structural databases, determining a conserved structural motif, despite the differences in the sequence, even among eukaryotes, archaea and bacteria. All data discussed in this review, both bibliographic and analytical, corroborate the functional importance of the PUA domain in RNA‐binding proteins.

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“…Although dyskerin mutation may increase cancer susceptibility, wild-type dyskerin and/or its mRNA are overexpressed in various sporadic cancer types, and high-levels may be associated with poor prognosis [14-16]. We and others previously demonstrated that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed human cell lines [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

Lin

Mobasher

Alawi

2014

Biochemical and Biophysical Research Communications

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Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita. Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.

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Dyskerin Overexpression in Human Hepatocellular Carcinoma Is Associated with Advanced Clinical Stage and Poor Patient Prognosis

Cited by 69 publications

References 31 publications

MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Protein universe containing a PUA RNA‐binding domain

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

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