Differential DNA Methylation of THOR and hTAPAS in the Regulation of hTERT and the Diagnosis of Cancer.

Autor: Ott P; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany., Araúzo-Bravo MJ; Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain.; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain., Hoffmann MJ; Department of Urology, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany., Poyet C; Department of Urology, University Hospital Zurich, 8091 Zurich, Switzerland., Bendhack ML; Department of Urology, University Hospital, Positivo University, Curitiba 80420-011, Brazil., Santourlidis S; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany., Erichsen L; Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany.; Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Sep 08; Vol. 14 (18). Date of Electronic Publication: 2022 Sep 08.
DOI: 10.3390/cancers14184384
Abstrakt: Background: Although DNA methylation in the gene promoters usually represses gene expression, the TERT hypermethylated oncological region (THOR) located 5' of the hTERT gene is hypermethylated when hTERT is expressed in diverse cancer types, including urothelial cancer (UC).
Methods: Comprehensive MeDIP and DNA methylation array analyses complemented by the technically independent method of bisulfite genomic sequencing were applied on pathologically reviewed and classified urothelial carcinoma specimens and healthy urothelial tissue samples to reveal the methylation status of THOR in detail.
Results: The detailed DNA methylation profiles reveal the exact positions of differentially methylated CpG dinucleotides within THOR in urothelial cancer and provide evidence ofa diverging role of methylation of these CpGs in the regulation of hTERT . In particular, our data suggest a regulating mechanism in which THOR methylation acts on hTERT expression through epigenetic silencing of the lncRNA hTERT antisense promoter-associated ( hTAPAS ), which represses hTERT .
Conclusions: These findings precisely define the most differentially methylated CpGs of THOR in early urothelial cancer, enabling optimal design of Methylation-Specific PCR (MSPCR) primers to reliably probe these methylation differences for diagnostic and prognostic purposes. In addition, this strategy presents a prime example that is also applicable to many other malignancies. Finally, the first evidence for the underlying epigenetic mechanism regulating hTERT expression through the methylation status of THOR is provided.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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