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Direct circMAN1A2(2,3,4,5)-CENPB mRNA interaction regulates cell proliferation and cancer progression

Mei Cao1, Guo-Hua Yuan2, Shi-Meng Cao3

  • 1Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Nature Communications
|September 29, 2025
PubMed

Insights

Alternative circularization (AC) generates multiple circRNAs from single genes. A specific AC circRNA, circMAN1A2(2,3,4,5), promotes colorectal cancer (CRC) progression by stabilizing CENPB mRNA, offering a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Genomics
  • Cancer Research

Background:

  • Covalently closed circular RNAs (circRNAs) arise from exon back-splicing.
  • Alternative circularization (AC) generates multiple circRNAs from a single gene locus.
  • The functions of most AC circRNAs are largely unknown.

Purpose of the Study:

  • To investigate the landscape of AC circRNAs in various cell lines and colorectal cancer (CRC) tissues.
  • To identify predominantly expressed circRNAs (pe-circRNAs) within AC gene loci.
  • To elucidate the function and mechanism of a specific AC circRNA, circMAN1A2(2,3,4,5), in CRC.

Main Methods:

  • Profiling of AC circRNA expression across multiple cell lines and CRC tissues.
  • Identification of pe-circRNAs in AC gene loci.
  • Mechanistic studies involving RNA-RNA interaction, mRNA stability assays, and locked nucleic acid inhibition.

Main Results:

  • Identified pe-circRNAs in AC gene loci, with predominantly cell-type-specific expression for most.
  • Discovered circMAN1A2(2,3,4,5) as a universally expressed pe-circRNA with a significant role in cell proliferation and CRC progression.
  • Demonstrated that circMAN1A2(2,3,4,5) enhances CENPB mRNA stability via interaction with its 3' UTR, mediated by IGF2BP2.
  • Showed that inhibiting circMAN1A2(2,3,4,5) represses CRC progression.

Conclusions:

  • AC circRNAs are prevalent and diverse.
  • circMAN1A2(2,3,4,5) is a key regulator of cell proliferation and CRC progression.
  • Targeting circMAN1A2(2,3,4,5) presents a potential therapeutic strategy for colorectal cancer.

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