The Long Noncoding RNA TTTY15, Which Is Located on the Y Chromosome, Promotes Prostate Cancer Progression by Sponging let-7

Abstract

Background: The link between prostate cancer (PCa) development and aberrant expression of genes located on the Y chromosome remains unclear.

Objective: To identify Y-chromosomal long noncoding RNAs (lncRNAs) with critical roles in PCa and to clarify the corresponding mechanisms.

Design, setting, and participants: Aberrantly expressed lncRNAs on the Y chromosome were identified using transcriptome analysis of PCa clinical samples and cell lines. Biological functions and molecular mechanisms of the lncRNAs were revealed using in vitro and in vivo experimental methods.

Outcome measurements and statistical analysis: Experiments and outcome measurements were performed in duplicate or triplicate. Wilcoxon signed-rank test was employed for comparison of RNA levels in clinical cohorts. Analysis of variance was employed for comparisons among multiple groups.

Results and limitations: In most patients with PCa, TTTY15 was the most elevated lncRNA located on the Y chromosome. Knockout of this lncRNA by two different CRISPR-Cas9 strategies suppressed PCa cell growth both in vitro and in vivo. TTTY15 promoted PCa by sponging the microRNA let-7, consequently increasing CDK6 and FN1 expression. FOXA1 is an upstream regulatory factor of TTTY15 transcription.

Conclusions: The Y-chromosomal lncRNA TTTY15 was upregulated in most PCa tissues and could promote PCa progression by sponging let-7.

Patient summary: We found that TTTY15 levels were frequently elevated in prostate cancer (PCa) tissues compared with those in paracancerous normal tissues in a large group of PCa patients, and we observed a tumour suppressive effect after TTTY15 knockout using CRISPR/Cas9. These results may have therapeutic implications for PCa patients.

Keywords: CRISPR/Cas9; Long noncoding RNAs; Prostate cancer; TTTY15; Y chromosome.