1. Academic Validation
  2. The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis

The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis

  • Cell Signal. 2022 Nov 18;110527. doi: 10.1016/j.cellsig.2022.110527.
Jiani He 1 Changming Dong 2 Hao Zhang 2 Yuanjun Jiang 2 Tao Liu 2 Xiaojun Man 3
Affiliations

Affiliations

  • 1 Department of Surgical Oncology and Breast Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning, PR China.
  • 2 Department of Urology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, PR China; Institute of Urology, China Medical University, Shenyang 110001, Liaoning, PR China.
  • 3 Department of Urology, The First Hospital of China Medical University, Shenyang 110001, Liaoning, PR China; Institute of Urology, China Medical University, Shenyang 110001, Liaoning, PR China. Electronic address: [email protected].
Abstract

Background: Overexpression of TFAP2A has been linked to increased lymph node metastasis in basal-squamous bladder Cancer. However, its downstream targets in bladder urothelial carcinoma (BLCA), the most malignant Cancer of the urinary tract, remain unclear. In the current study, we aim to explore the function and mechanism of TFAP2A in BLCA.

Methods: TFAP2A expression and the prognostic significance in BLCA was analyzed using TCGA and GTEX projects. TFAP2A was knocked-down in BLCA cells to study its impact on glucose uptake, lactate and ATP production, expression of HK2, and the number of vascular meshes formed by HUVEC. The target long noncoding RNAs (lncRNAs) of TFAP2A were predicted by bioinformatics tools, followed by ChIP-qPCR and luciferase assays. The downstream targets of TPRG1-AS1 were analyzed by microarray analysis. Rescue experiments were conducted for validation.

Results: TFAP2A upregulation in BLCA predicted dismal survival of patients. Loss of TFAP2A inhibited glycolysis (as evidenced by reduced glucose uptake, lactate, ATP production, and the expression of HK2) and angiogenesis (decreased number of vascular meshes formed by HUVEC). TFAP2A promoted the transcription of TPRG1-AS1. TPRG1-AS1 reversed the inhibitory effect of TFAP2A knockdown on glycolysis and angiogenesis in BLCA cells. TPRG1-AS1 inhibited the transcription of CRTAC1 by recruiting a DNA Methyltransferase to the promoter of CRTAC1 and increasing the DNA methylation of its promoter. CRTAC1 inhibited glycolysis and angiogenesis in BLCA cells. TFAP2A silencing curbed tumor growth in vivo via the TPRG1-AS1/CRTAC1 axis.

Conclusion: TFAP2A reduces CRTAC1 expression by promoting TPRG1-AS1 transcription, thereby expediting BLCA glycolysis and angiogenesis.

Keywords

Bladder urothelial carcinoma; CRTAC1; DNMT3A; Long noncoding RNA TPRG1-AS1; TFAP2A.

Figures
Products