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

Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2215132120. doi: 10.1073/pnas.2215132120. Epub 2023 Mar 24.


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.

Keywords: Nedd4L; YBX1; circRNA; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Humans
  • RNA, Circular / genetics
  • RNA, Circular / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Y-Box-Binding Protein 1 / genetics
  • Y-Box-Binding Protein 1 / metabolism


  • Ubiquitin-Protein Ligases
  • RNA, Circular
  • YBX1 protein, human
  • Y-Box-Binding Protein 1