Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation

Mol Cancer. 2022 Apr 2;21(1):92. doi: 10.1186/s12943-022-01570-4.


Background: Circular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure.

Methods: RNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments.

Results: Here, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/β-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 - + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin-proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with β-catenin protein was enhanced via suppressing the β-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus.

Conclusion: Our findings manifested a novel circMTCL1-C1QBP-β-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC.

Keywords: C1QBP; Laryngeal neoplasms; Ubiquitylation; circRNA MTCL1; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms* / genetics
  • Humans
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Mitochondrial Proteins / genetics
  • RNA, Circular* / genetics
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • C1QBP protein, human
  • C1qbp protein, mouse
  • Carrier Proteins
  • MTCL1 protein, human
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • RNA, Circular
  • Ubiquitin
  • beta Catenin