circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1

作者：Shuang Chen, Ke Li, Jiawei Guo, Hai‐Ning Chen, Yue Ming, Jin Yang, Fuyan Xu, Tingting Zhang, Yang Yang, Zixia Ye, Wenrong Liu, Hulin Ma, Jian Cheng, Jiankang Zhou, Zhang Li, Shu Yi Shen, Lunzhi Dai, Zong‐Guang Zhou, Heng Xu, Yong Peng · 发表于：Proceedings of the National Academy of Sciences · 年份：2023 · DOI：10.1073/pnas.2215132120 · 被引用次数：94 · 研究领域：Circular RNAs in diseases、Galectins and Cancer Biology、MicroRNA in disease regulation

Distant metastasis is a major contributor to cancer-related mortality. However, the role of circRNAs in this process remains unclear. Herein, we profiled the circRNA expression in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGFβ-responsive circRNAs, circNEIL3 (hsa_circ_0001460) was identified as a TGFβ-repressive and metastasis-related circRNA. Functionally, circNEIL3 effectively inhibited tumor metastasis in both and in vivo and in vivo models of various cancer types. Mechanistically, circNEIL3 exerts its metastasis-repressive function through its direct interaction with oncogenic protein, Y-box-binding protein 1 (YBX1), which consequently promotes the Nedd4L-mediated proteasomal degradation of YBX1. Importantly, circNEIL3 expression was negatively correlated to YBX1 protein level and metastatic tendency in CRC patient samples. Collectively, our findings indicate the YBX1-dependent antimetastatic function of circNEIL3 and highlight the potential of circNEIL3 as a biomarker and therapeutic option in cancer treatment.