1. Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
2. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
# Shanshan Liu and Jiashu Li contribute equally to this work.
Metabolic dysregulation has been identified as one of the hallmarks of cancer biology. Based on metabolic heterogeneity between bladder cancer tissues and adjacent tissues, we discovered several potential driving factors for the bladder cancer occurrence and development. Metabolic genomics showed purine metabolism pathway was mainly accumulated in bladder cancer. Long noncoding RNA urothelial carcinoma-associated 1 (LncRNA UCA1) is a potential tumor biomarker for bladder cancer diagnosis and prognosis, and it increases bladder cancer cell proliferation, migration, and invasion via the glycolysis pathway. However, whether UCA1 plays a role in purine metabolism in bladder cancer is unknown. Our findings showed that UCA1 could increase the transcription activity of guanine nucleotide de novo synthesis rate limiting enzyme inosine monophosphate dehydrogenase 1 (IMPDH1) and inosine monophosphate dehydrogenase 2 (IMPDH2), triggering in guanine nucleotide metabolic reprogramming. This process was achieved by UCA1 recruiting the transcription factor TWIST1 which binds to the IMPDH1and IMPDH2 promoter region. Increased guanine nucleotide synthesis pathway products stimulate RNA polymerase-dependent production of pre-ribosomal RNA and GTPase activity in bladder cancer cells, hence increasing bladder cancer cell proliferation, migration, and invasion. We have demonstrated that UCA1 regulates IMPDH1/2-mediated guanine nucleotide production via TWIST1, providing additional evidence of metabolic reprogramming.
Keywords: bladder cancer, UCA1, IMPDH, guanine nucleotide, metabolism