circTP63-N suppresses the proliferation and metastasis of nasopharyngeal carcinoma via engaging with HSP90AB1 to modulate the YAP1/Hippo signaling pathway

Dan Wang; Sicheng Zuo; Junshang Ge; Hongke Qu; Jie Wu; Na Yi; Lei Shi; Yumin Wang; Yongzhen Mo; Chunmei Fan; Yi He; Pan Chen; Ming Zhou; Bo Xiang; Wei Xiong; Wenjia Guo; Zhaoyang Zeng; Can Guo

doi:10.1007/s11427-023-2737-2

circTP63-N suppresses the proliferation and metastasis of nasopharyngeal carcinoma via engaging with HSP90AB1 to modulate the YAP1/Hippo signaling pathway

Sci China Life Sci. 2024 Dec 27. doi: 10.1007/s11427-023-2737-2. Online ahead of print.

Authors

Dan Wang^#^{1

2

3}, Sicheng Zuo^#^{1

2

3}, Junshang Ge^{1

2}, Hongke Qu^{1

2}, Jie Wu^{2

4}, Na Yi^{2

4}, Lei Shi^{1

2}, Yumin Wang^{1

2}, Yongzhen Mo^{1

2}, Chunmei Fan^{1

2}, Yi He¹, Pan Chen¹, Ming Zhou^{1

2}, Bo Xiang^{1

2}, Wei Xiong^{1

2

3}, Wenjia Guo^{5

6}, Zhaoyang Zeng^{7

8

9

10}, Can Guo^{11

12

13}

Affiliations

¹ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, China.
² Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, 410078, China.
³ Furong Laboratory, Changsha, 410078, China.
⁴ Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, China.
⁵ Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, China. wenjiaguo@xjmu.edu.cn.
⁶ Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, 830011, China. wenjiaguo@xjmu.edu.cn.
⁷ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, China. zengzhaoyang@csu.edu.cn.
⁸ Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, 410078, China. zengzhaoyang@csu.edu.cn.
⁹ Cancer Research Institute, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, China. zengzhaoyang@csu.edu.cn.
¹⁰ Xinjiang Key Laboratory of Translational Biomedical Engineering, Urumqi, 830011, China. zengzhaoyang@csu.edu.cn.
¹¹ NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410078, China. guocde@csu.edu.cn.
¹² Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, 410078, China. guocde@csu.edu.cn.
¹³ Furong Laboratory, Changsha, 410078, China. guocde@csu.edu.cn.

^# Contributed equally.

PMID: 39754006
DOI: 10.1007/s11427-023-2737-2

Abstract

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.

Keywords: HSP90AB1; YAP1/Hippo signaling pathway; circTP63-N; metastasis; nasopharyngeal carcinoma; proliferation.