Abstract
<div>Abstract<p>Splicing of the <i>hTERT</i> gene to produce the full-length (FL) transcript is necessary for telomerase enzyme activity and telomere-dependent cellular immortality in the majority of human tumors, including non–small cell lung cancer (NSCLC) cells. The molecular machinery to splice <i>hTERT</i> to the FL isoform remains mostly unknown. Previously, we reported that an intron 8 <i>cis-</i>element termed “direct repeat 8” (DR8) promotes FL <i>hTERT</i> splicing, telomerase, and telomere length maintenance when bound by NOVA1 and PTBP1 in NSCLC cells. However, some NSCLC cells and patient tumor samples lack NOVA1 expression. This leaves a gap in knowledge about the splicing factors and <i>cis-</i>elements that promote telomerase in the NOVA1-negative context. We report that DR8 regulates FL <i>hTERT</i> splicing in the NOVA1-negative and -positive lung cancer contexts. We identified splicing factor 3b subunit 4 (SF3B4) as an RNA <i>trans-</i>factor whose expression is increased in lung adenocarcinoma (LUAD) tumors compared with adjacent normal tissue and predicts poor LUAD patient survival. In contrast to normal lung epithelial cells, which continued to grow with partial reductions of SF3B4 protein, SF3B4 knockdown reduced <i>hTERT</i> splicing, telomerase activity, telomere length, and cell growth in lung cancer cells. SF3B4 was also demonstrated to bind the DR8 region of <i>hTERT</i> pre-mRNA in both NOVA1-negative and -positive NSCLC cells. These findings provide evidence that DR8 is a critical binding hub for <i>trans-</i>factors to regulate FL <i>hTERT</i> splicing in NSCLC cells. These studies help define mechanisms of gene regulation important to the generation of telomerase activity during carcinogenesis.</p>Implications:<p>Manipulation of a core spliceosome protein reduces telomerase/<i>hTERT</i> splicing in lung cancer cells and results in slowed cancer cell growth and cell death, revealing a potential therapeutic strategy.</p></div>
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