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a concise and structured summary of the article "Mechanisms and therapeutic implications of gene expression regulation by circRNA-protein interactions in cancer" published in Communications Biology (2025): PDF 

🔬 Overview

Circular RNAs (circRNAs) are a unique class of non-coding RNAs with a closed-loop structure. Emerging research highlights their crucial role in cancer by interacting with RNA-binding proteins (RBPs)—collectively known as circRNA-protein interactions (CPIs)—to regulate gene expression at various levels.

🧬 Biogenesis & Classification of circRNAs

  • Originates from back-splicing of precursor mRNAs.
  • Categories:
    • EcircRNAs (exonic, mostly cytoplasmic)
    • ciRNAs (intronic, nuclear)
    • EIciRNAs (exon-intron, nuclear)
    • Intergenic circRNAs
  • CircRNAs are highly stable, resistant to RNases, and often tissue-specific.

🔁 Biological Functions

  • Act as:
    • miRNA sponges
    • Scaffolds or recruiters for RBPs
    • Regulators of transcription & translation
    • Some even encode small peptides

🎯 Focus: circRNA-Protein Interactions (CPIs) in Cancer

CPIs affect tumor biology via:

  1. Transcription regulation
  2. Alternative splicing
  3. Translation control
  4. Subcellular localization of RBPs
  5. Post-translational modifications (PTMs)
  6. Drug resistance

🧾 Key Mechanisms and Examples

🧾 1. Transcription Modulation

  • circ-DONSON recruits NURF complex → activates SOX4 → promotes gastric cancer.
  • circIPO11 recruits TOP1 → activates GLI1 in liver cancer.
  • circRNF10 sequesters DHX15 → blocks p65-mediated oncogene transcription → suppresses breast cancer.

🧾 2. Alternative Splicing

  • circURI1 interacts with hnRNPM → affects VEGFA isoforms → suppresses gastric cancer metastasis.
  • circSMARCA5 interacts with SRSF1 → anti-angiogenesis in glioblastoma.

🧾 3. Translation Regulation

  • circPTPRA binds IGF2BP1 → destabilizes oncogenic mRNAs → suppresses bladder cancer.
  • circMYH9 destabilizes p53 pre-mRNA via hnRNPA2B1 → promotes colorectal cancer.

🧾 4. Subcellular Localization

  • circDCUN1D4 helps HuR translocate to cytoplasm → suppresses metastasis in lung adenocarcinoma.
  • circIMMP2L retains CtBP1 in nucleus → promotes esophageal cancer progression.

🧾 5. Post-Translational Modifications (PTMs)

  • Phosphorylation: circEIF3I binds SMAD3/AP2A1 → promotes pancreatic cancer.
  • Ubiquitination: circPDK1 recruits UBE20 → enhances pancreatic cancer progression.
  • Glycosylation, SUMOylation, Acetylation, Lactylation: Various circRNAs affect cancer via modifying key RBPs or enzymes.

🧾 6. Drug Resistance

  • circRNA-SORE binds YBX1 → stabilizes it → induces sorafenib resistance in hepatocellular carcinoma.
  • circITGB6 interacts with IGF2BP2/3 → induces cisplatin resistance in ovarian/colorectal cancer.

💊 Therapeutic Implications

  • CPIs represent potential biomarkers for cancer diagnosis.
  • Targeting CPIs (e.g., blocking specific circRNA-RBP interactions) could reverse drug resistance and suppress tumor growth.
  • The tertiary structure of circRNAs and their subcellular localizations may inform targeted drug design.

🔍 Unresolved Questions & Future Directions

  • How do circRNA binding sites and conformations influence CPI function?
  • Can CPIs be universally targeted across cancers?
  • What are the best delivery systems for circRNA-modulating therapies?