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Updated: Sep 29, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Downregulation and Hypermethylation of GABPB1 Is Associated with Aggressive Thyroid Cancer Features
Xiangling Xing1, Ninni Mu2, Xiaotian Yuan1,3
1Department of Medicine, Division of Hematology, Bioclinicum J6:20 and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 64 Solna, Sweden.
Abstract:
Promoter mutations of the telomerase reverse transcriptase (TERT) gene occur frequently in thyroid carcinoma (TC), including papillary (PTC) and anaplastic subtypes (ATC). Given that the ETS family transcription factors GABPA and GABPB1 activate the mutant TERT promoter and induce TERT expression for telomerase activation, GABPB1 has been proposed as a cancer therapeutic target to inhibit telomerase. Here, we sought to determine the role of GABPB1 in TC pathogenesis. In TC-derived cells carrying the mutated TERT promoter, GABPB1 knockdown led to diminished TERT expression but significantly increased invasive potentials in vitro and metastatic potential in a xenograft zebrafish model and altered expression of markers for epithelial-to-mesenchymal transition. GABPB1 expression was downregulated in aggressive TCs. Low GABPB1 expression correlated with its promoter hypermethylation, which in turn was also associated with shorter disease-free survival. Consistently, DNA methylation inhibitors enhanced GABPB1 expression, as observed upon reduced promoter methylation. Our results suggest that GABPB1 is required for TERT expression and telomerase activation, but itself serves as a tumor suppressor to inhibit TC progression. Furthermore, aberrant DNA methylation leads to GABPB1 silencing, thereby promoting TC aggressiveness. Thus, caution is needed if targeting GABPB1 for cancer therapy is considered.
Insights
GABPB1 is crucial for telomerase reverse transcriptase (TERT) expression in thyroid cancer. However, low GABPB1 levels promote tumor progression and metastasis, suggesting it acts as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Telomerase reverse transcriptase (TERT) promoter mutations are common in thyroid carcinoma (TC).
- ETS transcription factors GABPA and GABPB1 activate mutant TERT promoter, driving TERT expression and telomerase activation.
- GABPB1 has been investigated as a potential therapeutic target to inhibit telomerase in cancer.
Purpose of the Study:
- To investigate the role of GABPB1 in thyroid carcinoma (TC) pathogenesis.
- To determine if GABPB1 acts as a tumor suppressor or promoter in TC.
- To explore the relationship between GABPB1 expression, DNA methylation, and TC aggressiveness.
Main Methods:
- GABPB1 knockdown in TC-derived cells with mutated TERT promoter.
- In vitro invasion assays.
- Zebrafish xenograft model for metastasis assessment.
- Analysis of GABPB1 expression and promoter methylation in TC tissues.
- Treatment with DNA methylation inhibitors.
Main Results:
- GABPB1 knockdown reduced TERT expression but increased invasiveness and metastasis in TC models.
- GABPB1 expression was downregulated in aggressive TCs.
- Low GABPB1 expression correlated with promoter hypermethylation and shorter disease-free survival.
- DNA methylation inhibitors increased GABPB1 expression by reducing promoter methylation.
Conclusions:
- GABPB1 is necessary for TERT expression and telomerase activation but functions as a tumor suppressor in TC.
- Aberrant DNA methylation silences GABPB1, promoting TC aggressiveness.
- Targeting GABPB1 for cancer therapy requires careful consideration due to its tumor-suppressive role.
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