TERC Stimulates Fatty Acid Metabolism to Promote Bladder Cancer Progression.

UNLABELLED: Muscle-invasive bladder cancer is susceptible to metastasis and has a poor prognosis. A better understanding of the biological process and molecular mechanisms associated with bladder cancer aggressiveness could lead to the development of effective strategies to prevent metastasis. In this study, we identified that the long noncoding RNA telomerase RNA component (TERC) was significantly upregulated in invasive bladder urothelial carcinoma tissues. Loss of TERC inhibited the proliferation, migration, and invasion of bladder cancer cells in vitro and suppressed tumor growth in vivo. N6-methyladenosine modification mediated the upregulated TERC expression levels in bladder cancer cells. TERC facilitated nuclear export of polypyrimidine tract-binding protein 3 (PTBP3) through the nuclear pore complex, which enabled PTBP3 to bind to the 3' untranslated region of retinoid X receptor α (RXRA) mRNA. PTBP3 binding enhanced RXRA mRNA stability and upregulated its protein levels, leading to elevated expression of downstream fatty acid uptake-related molecules. Through this mechanism, TERC remodeled fatty acid metabolism and thereby promoted bladder cancer growth and invasion. Furthermore, TERC levels in exosomes were elevated in the urine and plasma of patients with urothelial carcinoma. High levels of urine exosomal TERC were associated with lymph node metastasis and larger tumor diameter, whereas high plasma exosomal TERC was linked to lymph node metastasis and high pathologic grade. Overall, these findings indicate that TERC represents a potential target for therapeutic development and a putative liquid biopsy biomarker for the diagnosis of urothelial carcinoma.

SIGNIFICANCE: TERC is a potential therapeutic target and biomarker in bladder cancer that undergoes m6A-mediated upregulation and remodels fatty acid metabolism by enhancing RXRA levels through nuclear export PTBP3 to promote tumor aggressiveness.