Male-Specific Long Noncoding RNA TTTY15 Inhibits Non-Small Cell Lung Cancer Proliferation and Metastasis via TBX4

Abstract

Gender affects cancer susceptibility. Currently, there are only a few studies on Y chromosome-linked long noncoding RNAs (lncRNAs), and the potential association between lncRNAs and cancers in males has not been fully elucidated. Here, we examined the expression of testis-specific transcript Y-linked 15 (<i>TTTY15</i>) in 37 males with non-small cell lung cancer (NSCLC), and performed circular chromosome conformation capture with next-generation sequencing to determine the genomic interaction regions of the <i>TTTY15</i> gene. Our results showed that the expression levels of <i>TTTY15</i> were lower in NSCLC tissues. Lower <i>TTTY15</i> expression levels were associated with Tumor-Node-Metastasis (TNM) stage. A <i>TTTY15</i> knockdown promoted malignant transformation of NSCLC cells. Based on the bioinformatics analysis of circular chromosome conformation capture data, we found that T-box transcription factor 4 (TBX4) may be a potential target gene of <i>TTTY15</i>. The RNA immunoprecipitation and chromatin immunoprecipitation results showed that <i>TTTY15</i> may interact with DNA (cytosine-5)-methyltransferase 3A (DNMT3A), and the <i>TTTY15</i> knockdown increased the binding of DNMT3A to the TBX4 promoter. We concluded that low <i>TTTY15</i> expression correlates with worse prognosis among patients with NSCLC. <i>TTTY15</i> promotes TBX4 expression via DNMT3A-mediated regulation. The identification of lncRNAs encoded by male-specific genes may help to identify potential targets for NSCLC therapy.