Characterization of human telomerase reverse transcriptase promoter methylation and transcription factor binding in differentiated thyroid cancer cell lines.
Alleles
Binding Sites
Cell Line, Tumor
CpG Islands
DNA Methylation
Gene Expression Regulation, Neoplastic
Humans
Mutation
Nucleotide Motifs
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins c-myc
/ metabolism
Telomerase
/ genetics
Thyroid Neoplasms
/ genetics
Transcription Factors
/ metabolism
Transcription Initiation Site
DNA methylation
promoter
telomerase
thyroid cancer
Journal
Genes, chromosomes & cancer
ISSN: 1098-2264
Titre abrégé: Genes Chromosomes Cancer
Pays: United States
ID NLM: 9007329
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
20
08
2018
revised:
04
01
2019
accepted:
14
01
2019
pubmed:
22
1
2019
medline:
10
1
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
Telomerase reverse transcriptase (TERT) activation plays an important role in cancer development by enabling the immortalization of cells. TERT regulation is multifaceted, and its promoter methylation has been implicated in controlling expression through alteration in transcription factor binding. We have characterized TERT promoter methylation, transcription factor binding, and TERT expression levels in five differentiated thyroid cancer (DTC) cell lines and six normal thyroid tissue samples by targeted bisulfite sequencing, ChIP-qPCR, and qRT-PCR. DTC cell lines express varying levels of TERT and exhibit TERT promoter methylation patterns similar to patterns seen in other telomerase positive cancer cell lines. The minimal promoter immediately surrounding the transcription start site is hypomethylated, while further upstream portions show dense methylation. In contrast, the TERT promoter in normal thyroid tissue is largely unmethylated throughout and expresses TERT minimally. Transcription factor binding is also affected by TERT mutation status. The E-twenty-six (ETS) factor GABPA exhibits TERT binding in the TERT mutant DTC cells only, and allele-specific methylation patterns at the minimal promoter were observed as well, which may indicate allele-specific factor recruitment at the minimal promoter. Furthermore, we identified binding sites for activators MYC and GSC in the hypermethylated upstream region, pointing to its possible importance in TERT regulation. Overall, TERT expression and telomerase activity depend on the interplay of multiple regulatory mechanisms including TERT promoter methylation, mutation status, and recruitment of transcription factors. This work explores of the interplay between these regulatory mechanisms and offers insight into cellular control of active telomerase in human cancer.
Identifiants
pubmed: 30664813
doi: 10.1002/gcc.22735
pmc: PMC6621557
mid: NIHMS1017477
doi:
Substances chimiques
Proto-Oncogene Proteins c-myc
0
Transcription Factors
0
TERT protein, human
EC 2.7.7.49
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
530-540Subventions
Organisme : NCI NIH HHS
ID : T32 CA153952
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA140311
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007057
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136577
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007445
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA130840
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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