Abstract
Simple SummaryPromoter 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.
Highlights
Telomerase is a ribonucleoprotein lengthening telomeric DNA sequences at the termini of human linear chromosomes, and telomerase reverse transcriptase (TERT) is a rate-limiting component of the telomerase enzyme [1–4]
Our recent study showed that GABPA knockdown leads to diminished TERT expression, whereas it facilitates the invasive phenotype in thyroid carcinoma (TC) cells [27]
To determine if this is the case for GABPB1, the partner of GABPA, we inhibited GABPB1 expression in Uhth-74 and U-hth-104 cells using RNA interference (RNAi) technique and, at the same time, included GABPA RNA Interference (RNAi) as an additional control to further verify the specificity of these siRNAs (Figure 1A)
Summary
Telomerase is a ribonucleoprotein lengthening telomeric DNA sequences at the termini of human linear chromosomes, and telomerase reverse transcriptase (TERT) is a rate-limiting component of the telomerase enzyme [1–4]. The mutations occur at two hotspots (−124 and −146 upstream of ATG), and both are C > T transitions, denoted C228T and C250T, respectively [8,9] These mutations create de novo ETS binding motifs that are mainly recognized and bound by the ETS family transcription factors GABP sub-group members [10,11]. The GABP factors, including the DNA binding domain-containing GABPα (GABPA) and the trans-activation domain-bearing GABPβ (GABPB), can act as a heterodimer or heterotetramer to activate the transcription of their target genes [11,12]. GABPB1 knockout inhibits TERT expression and telomerase activity in TERT promoter-mutated glioblastoma cells, disrupting telomere length maintenance through which apoptosis is induced [13]. Telomerase/TERT repression by inhibiting GABPB1 expression was proposed as a therapeutic strategy against cancer carrying a mutated TERT promoter [13]
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