Circ MTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3

Int J Mol Sci. 2024 Feb 29;25(5):2817. doi: 10.3390/ijms25052817.

Abstract

Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.

Keywords: CircRNAs; MTA2; UCHL3; gastric cancer; ubiquitination.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases / metabolism
  • Humans
  • Proteolysis
  • Repressor Proteins / genetics
  • Stomach Neoplasms* / pathology
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Repressor Proteins
  • Histone Deacetylases
  • MTA2 protein, human
  • UCHL3 protein, human
  • Ubiquitin Thiolesterase

Grants and funding

This study was supported by the Natural Science Foundation of Hubei Province (No. 2020CFB789; No. 2021CFB594) and the Scientific Research Project of the Health Commission of Hubei Province (Grant No. WJ2019M166).