Circular RNAs(circRNAs)play pivotal roles in the development and progression of various diseases,including malignant tumors.However,the biological functions and the underlying mechanisms of many circRNAs remain elusiv...Circular RNAs(circRNAs)play pivotal roles in the development and progression of various diseases,including malignant tumors.However,the biological functions and the underlying mechanisms of many circRNAs remain elusive.In this study,we identified a novel circRNA,circTP63-N,generated through the splicing of exons 2–4 of the TP63 gene in nasopharyngeal carcinoma(NPC).circTP63-N was found to be downregulated in clinical samples of NPC.Both in vitro and in vivo experiments unequivocally demonstrated that circTP63-N inhibits the proliferation and metastasis of NPC cells.Further investigations revealed that circTP63-N interacted with the HSP90AB1 protein,leading to the recruitment of LATS/YAP1 proteins.This,in turn,induced phosphorylation and ubiquitination-dependent degradation of YAP1,resulting in reduced nuclear translocation of YAP1 and inhibition of the transcriptional activation of downstream oncogenic genes,including INHBA,MMP3,and CCNE2.Our findings highlight the identification of circTP63-N,a novel circRNA encoded by an important tumor-relevant gene TP63 and elucidate its molecular mechanism as a tumor suppressor in NPC.These insights offer novel potential molecular markers and therapeutic targets for the clinical diagnosis and treatment of NPC.展开更多
基金supported by the National Natural Science Foundation of China(82273174,82072374)the Key Research and Development Program of Hunan Province(2023DK2001,2023SK2004,2023ZJ1120-2)+1 种基金the China Postdoctoral Science Foundation(2024M763705)Key R&D Program in Xinjiang Uygur Autonomous Region(2022B03019-4).
文摘Circular RNAs(circRNAs)play pivotal roles in the development and progression of various diseases,including malignant tumors.However,the biological functions and the underlying mechanisms of many circRNAs remain elusive.In this study,we identified a novel circRNA,circTP63-N,generated through the splicing of exons 2–4 of the TP63 gene in nasopharyngeal carcinoma(NPC).circTP63-N was found to be downregulated in clinical samples of NPC.Both in vitro and in vivo experiments unequivocally demonstrated that circTP63-N inhibits the proliferation and metastasis of NPC cells.Further investigations revealed that circTP63-N interacted with the HSP90AB1 protein,leading to the recruitment of LATS/YAP1 proteins.This,in turn,induced phosphorylation and ubiquitination-dependent degradation of YAP1,resulting in reduced nuclear translocation of YAP1 and inhibition of the transcriptional activation of downstream oncogenic genes,including INHBA,MMP3,and CCNE2.Our findings highlight the identification of circTP63-N,a novel circRNA encoded by an important tumor-relevant gene TP63 and elucidate its molecular mechanism as a tumor suppressor in NPC.These insights offer novel potential molecular markers and therapeutic targets for the clinical diagnosis and treatment of NPC.
