circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity

Nat Commun. 2021 Jan 12;12(1):295. doi: 10.1038/s41467-020-20527-z.

Abstract

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation
  • DEAD Box Protein 58 / metabolism
  • Disease Progression*
  • Down-Regulation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Biological
  • Neoplasm Metastasis
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Stability
  • Proteolysis
  • RNA, Circular / genetics
  • RNA, Circular / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism*
  • Receptors, Immunologic
  • Transcription Factors / metabolism
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • IGF2BP2 protein, human
  • QKI protein, human
  • RNA, Circular
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Immunologic
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ubiquitin
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • RIGI protein, human
  • DEAD Box Protein 58