Downregulation and Hypermethylation of GABPB1 Is Associated with Aggressive Thyroid Cancer Features

Simple Summary Promoter mutations of the telomerase reverse transcriptase (TERT) gene have been suggested as an oncogenic event in various cancers, including thyroid cancer (TC). GABPB1 is reported to activate TERT gene expression and has been proposed as a cancer therapeutic target. The aim of this study is to explore the fate of TC cells after disruption of GABPB1 and its role in TC. We found that besides the reported oncogenic role of GABPB1 in activating TERT, it also has tumor-suppressive functions in TC. Therefore, targeting GABPB1 for cancer therapy should be cautious since it may counteract its tumor-suppressive functions. 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.