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

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 expres-sion in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGF beta-responsive circRNAs, circ-NEIL3 (hsa_circ_0001460) was identified as a TGF beta-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 onco-genic 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.SignificanceCircular RNAs (circRNAs) play important roles in tumor metastasis. Our results identified circNEIL3 (hsa_circ_0001460) as a TGF beta-repressive circRNA and also down-regulated in metastatic tumor lesions and demonstrated that circNEIL3 potently represses tumor metastasis in vitro and in vivo. circNEIL3 promoted Nedd4L-mediated proteasomal degradation of YBX1 through its direct interaction with YBX1. Our study provides a reported association of circRNA, protein stability, and metastasis and sheds lights on the molecular mechanism of circRNA in metastasis.