PITX1 protein interacts with ZCCHC10 to regulate <i>hTERT</i> mRNA transcription

Abstract

<div><p>Telomerase is a ribonucleoprotein ribonucleic enzyme that is essential for cellular immortalization <i>via</i> elongation of telomere repeat sequences at the end of chromosomes. Human telomerase reverse transcriptase (<i>hTERT</i>), the catalytic subunit of telomerase holoenzyme, is a key regulator of telomerase activity. Telomerase activity, which has been detected in the majority of cancer cells, is accompanied by <i>hTERT</i> expression, suggesting that this enzyme activity contributes to an unlimited replication potential of cancer cells <i>via</i> regulation of telomere length. Thus, <i>hTERT</i> is an attractive target for cancer-specific treatments. We previously reported that pared-like homeodomain 1 (<i>PITX1</i>) is a negative regulator of <i>hTERT</i> through direct binding to the <i>hTERT</i> promoter. However, the mechanism by which the function of <i>PITX1</i> contributes to transcriptional silencing of the <i>hTERT</i> gene remains to be clarified. Here, we show that PITX1 and zinc finger CCHC-type containing 10 (ZCCHC10) proteins cooperate to facilitate the transcriptional regulation of the <i>hTERT</i> gene by functional studies <i>via</i> FLAG pull-down assay. Co-expression of <i>PITX1</i> and <i>ZCCHC10</i> resulted in inhibition of <i>hTERT</i> transcription, in melanoma cell lines, whereas mutate-deletion of homeodomain in PITX1 that interact with ZCCHC10 did not induce similar phenotypes. In addition, ZCCHC10 expression levels showed marked decrease in the majority of melanoma cell lines and tissues. Taken together, these results suggest that ZCCHC10-PITX1 complex is the functional unit that suppresses <i>hTERT</i> transcription, and may play a crucial role as a novel tumor suppressor complex.</p></div>