Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the nasopharyngeal epithelium. Due to its concealed location and nonspecific early symptoms, most patients present with lymph node metastasis at the time of diagnosis. Recurrence and metastasis are the primary factors contributing to the poor therapeutic outcomes of NPC. The development and progression of NPC involve abnormal expression of numerous oncogenes and tumor suppressor genes, but its precise pathogenesis remains unclear. Circular RNAs (circRNAs) play a significant role in the occurrence and progression of malignant tumors; however, the functions and mechanisms of many circRNAs in NPC remain largely unexplored.
Recently, Science China Life Sciences published online a research article titled "circTP63-N suppresses the proliferation and metastasis of nasopharyngeal carcinoma via engaging with HSP90AB1 to modulate the YAP1/Hippo signaling pathway," co-authored by Professors Zhaoyang Zeng and Can Guo from the Xiangya School of Basic Medical Sciences, Central South University, and Researcher Wenjia Guo from Xinjiang Medical University. The study reported a novel circular RNA, circTP63-N, generated by back-splicing exons 2–4 of the TP63 gene. This circRNA is significantly downregulated in clinical samples of NPC, and restoring its expression effectively inhibits NPC cell proliferation and metastasis.
TP63, a member of the TP53 gene family, is highly expressed in nearly 100% of NPC tissues and plays a crucial role in the tumor's development and progression. The TP63 gene exhibits a complex structure and diverse alternative splicing forms. It contains two independent promoters: one upstream of exon 1, driving the transcription of TAp63, and another within intron 3, near the specific exon 3 of ΔNp63, driving the transcription of ΔNp63. These two promoters independently generate two distinct isoforms: TAp63 and ΔNp63. Additionally, TAp63 and ΔNp63 undergo further alternative splicing to produce multiple transcripts, including α, β, and γ variants.
Previous studies reported that exons 11 and 12 of the TP63 gene could splice into a circular RNA, circTP63, which exerts oncogenic functions in various tumors. However, the research team found that circTP63 expression is extremely low or undetectable in NPC cell lines, NPC biopsy samples, and normal nasopharyngeal epithelium. They identified a novel circular RNA derived from exons 2–4 of TP63, named circTP63-N to distinguish it from the previously reported circTP63. CircTP63-N is highly expressed in normal nasopharyngeal epithelium but significantly downregulated in NPC tissues.
In vitro and in vivo experiments demonstrated that circTP63-N directly binds to the HSP90AB1 protein, facilitating the recruitment of LATS1/2 and YAP1 proteins. This process induces the phosphorylation and ubiquitination-mediated degradation of YAP1, thereby reducing its nuclear translocation. Consequently, this inhibits the transcriptional activation of downstream genes related to the extracellular matrix (e.g., INHBA and MMP3) and cell cycle (e.g., CCNE2), effectively suppressing the proliferation, invasion, and migration of NPC cells. This discovery provides new insights into the functional regulation of the TP63 gene and its role in NPC, offering potential targets for the diagnosis and treatment of NPC.
Professors Zhaoyang Zeng and Can Guo from the Xiangya School of Basic Medical Sciences, Central South University, and Researcher Wenjia Guo from Xinjiang Medical University are the corresponding authors of this study. Dr. Dan Wang, a postdoctoral researcher, and Sicheng Zuo, a master's student from the Cancer Research Institute of Central South University, are the co-first authors. This research received substantial support from Professors Guiyuan Li, Wei Xiong, and Bo Xiang from the Cancer Research Institute of Central South University.
