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Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.
Clin. Epigenet. 10:27 (2018)
Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.
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6.091
1.049
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Uhrf1 ; Hepatoblastoma ; Dnmt1 ; Usp7 ; Histone Methylation ; Dna Methylation ; Epigenetic Silencing ; Tumor Suppressor Genes ; Biomarker; Dna Methylation; Histone Modifications; Ubiquitin-like; Liver-cancer; Protein; Dnmt1; Proliferation; Contributes; Oncogenesis; Inhibition
Language
english
Publication Year
2018
HGF-reported in Year
2018
ISSN (print) / ISBN
1868-7075
e-ISSN
1868-7083
Journal
Clinical Epigenetics
Quellenangaben
Volume: 10,
Issue: 1,
Article Number: 27
Publisher
Springer
Publishing Place
Berlin : Heidelberg
Reviewing status
Peer reviewed
Institute(s)
Institute of Human Genetics (IHG)
POF-Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-500700-001
WOS ID
WOS:000427080000001
Scopus ID
85042871570
PubMed ID
29507645
Erfassungsdatum
2018-05-24