ArticleCancer cell international2024
TERT upstream promoter methylation regulates TERT expression and acts as a therapeutic target in TERT promoter mutation-negative thyroid cancer.
Article in Cancer cell international, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Synergistic role of molecular imaging and genomics in thyroid cancer management: from diagnosis to personalized treatment.Journal of translational medicine · 2026Review
- Advances and clinical potential of epigenome editing.Cellular and molecular life sciences : CMLS · 2026Review
- The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer.Cell death discovery · 2026Review
- CHD4 and NOX4 expression in thyroid tumor tissues.Exploration of targeted anti-tumor therapy · 2026Article
- THOR methylation as a pan-cancer mechanism ofFrontiers in oncology · 2026Review
- Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression.Cancer gene therapy · 2025Article
- Telomere Maintenance and DNA Repair: A Bidirectional Relationship in Cancer Biology and Therapy.Cancers · 2025Review
- Case Report: Novel mutation in CHD4 triggers occult breast cancer with bone metastases.Frontiers in oncology · 2025Article
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Authors and funding
6 authors.
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Abstract
backgroundDNA hypermethylation and hotspot mutations were frequently observed in the upstream and core promoter of telomerase reverse transcriptase (TERT), respectively, and they were associated with increased TERT expression and adverse clinical outcomes in thyroid cancer. In TERT promoter mutant cancer cells, the hypomethylated TERT mutant allele was active and the hypermethylated TERT wild-type allele was silenced. However, whether and how the upstream promoter methylation regulates TERT expression in TERT mutation-negative cells were largely unknown.
methodsDNA demethylating agents 5-azacytidine and decitabine and a genomic locus-specific demethylation system based on dCas9-TET1 were used to assess the effects of TERT upstream promoter methylation on TERT expression, cell growth and apoptosis of thyroid cancer cells. Regulatory proteins binding to TERT promoter were identified by CRISPR affinity purification in situ of regulatory elements (CAPTURE) combined with mass spectrometry. The enrichments of selected regulatory proteins and histone modifications were evaluated by chromatin immunoprecipitation.
resultsThe level of DNA methylation at TERT upstream promoter and expression of TERT were significantly decreased after treatment with 5-azacytidine or decitabine in TERT promoter wild-type thyroid cancer cells. Genomic locus-specific demethylation of TERT upstream promoter induced TERT downregulation, along with cell apoptosis and growth inhibition. Consistently, demethylating agents sharply inhibited the growth of thyroid cancer cells harboring hypermethylated TERT but had little effect on cells with TERT hypomethylation. Moreover, we identified that the chromatin remodeling protein CHD4 binds to methylated TERT upstream promoter and promotes its transcription by suppressing the enrichment of H3K9me3 and H3K27me3 at TERT promoter.
conclusionsThis study uncovered the mechanism of promoter methylation mediated TERT activation in TERT promoter mutation-negative thyroid cancer cells and indicated TERT upstream promoter methylation as a therapeutic target for thyroid cancer.
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