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

Abstract

Promoter mutations of the telomerase reverse transcriptase (<i>TERT</i>) 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 <i>TERT</i> promoter and induce <i>TERT</i> 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 <i>TERT</i> promoter, GABPB1 knockdown led to diminished <i>TERT</i> 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. <i>GABPB1</i> expression was downregulated in aggressive TCs. Low <i>GABPB1</i> expression correlated with its promoter hypermethylation, which in turn was also associated with shorter disease-free survival. Consistently, DNA methylation inhibitors enhanced <i>GABPB1</i> expression, as observed upon reduced promoter methylation. Our results suggest that GABPB1 is required for <i>TERT</i> 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.