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作者

Xiangling Xing, Ninni Mu, Xiaotian Yuan, Na Wang, C Christofer Juhlin, Klas Strååt, Catharina Larsson, Shi Yong Neo, Dawei Xu

作者单位

Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Singapore 138648, Singapore. Department of Medicine-Huddinge, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Laboratory Animal Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China. Department of Pathology and Cancer Diagnostics, Karolinska University Hospital-Solna, SE-171 76 Stockholm, Sweden. Department of Oncology-Pathology, BioClinicum J6:20, Karolinska Institutet, SE-171 64 Solna, Sweden. Affiliations Department 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.

刊名

Cancers

年份

2022

卷号

Vol.14 No.6

页码

1385

ISSN

2072-6694

关键词

DNA methylation GABPA GABPB1 TERT telomerase thyroid carcinoma.

摘要

Promoter mutations of the telomerase reverse transcriptase gene occur frequently in thyroid carcinoma , including papillary and anaplastic subtypes . 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 pr...更多

Promoter mutations of the telomerase reverse transcriptase gene occur frequently in thyroid carcinoma , including papillary and anaplastic subtypes . 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.收起

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