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Beck, A.* ; Trippel, F.* ; Wagner, A.* ; Joppien, S.* ; Felle, M.* ; Vokuhl, C.* ; Schwarzmayr, T. ; Strom, T.M. ; von Schweinitz, D.* ; Längst, G.* ; Kappler, R.*

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.

Clin. Epigenet. 10:27 (2018)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 1868-7075
e-ISSN 1868-7083
Zeitschrift Clinical Epigenetics
Quellenangaben Band: 10, Heft: 1, Seiten: , Artikelnummer: 27 Supplement: ,
Verlag Springer
Verlagsort Berlin : Heidelberg
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
DOI 10.1186/s13148-018-0462-7
WOS ID WOS:000427080000001
Scopus ID 85042871570
PubMed ID 29507645
Erfassungsdatum 2018-05-24
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