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YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in

Yang Zhao1,2, Hongchao Zhao3, Danhuan Zhang4

  • 1Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.

ACS Chemical Biology
|June 16, 2022
PubMed

Insights

YTHDF3 is highly expressed in oxaliplatin-resistant colorectal cancer (CRC). It enhances gene translation by coordinating with eIF2AK2, offering a new target for overcoming chemo-resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Oxaliplatin is a key first-line chemotherapy for colorectal cancer (CRC).
  • Chemo-resistance to oxaliplatin is a significant challenge in CRC treatment.
  • N6-methyladenosine (m6A) RNA modification plays roles in various cellular functions, but its role in CRC chemo-resistance is unclear.

Purpose of the Study:

  • To investigate the role of m6A RNA-binding protein YTHDF3 in oxaliplatin resistance in CRC.
  • To elucidate the molecular mechanism by which YTHDF3 influences gene translation in chemo-resistant CRC cells.

Main Methods:

  • Analysis of YTHDF3 expression in oxaliplatin-resistant (OXAR) CRC tissues and cells.
  • Investigation of YTHDF3's interaction with m6A-modified RNAs and eukaryotic translation initiation factor 3 subunit A (eIF3A).
  • Determination of the role of eukaryotic translation initiation factor 2 alpha kinase 2 (eIF2AK2) in the YTHDF3/eIF3A complex stability.

Main Results:

  • YTHDF3 expression is elevated in OXAR CRC tissues and cells.
  • YTHDF3 binds to m6A-modified RNAs in their 5' untranslated region, promoting the translation of resistance-associated genes.
  • eIF2AK2 acts as a bridge between YTHDF3 and eIF3A, stabilizing their complex and enhancing translation in OXAR CRC cells.

Conclusions:

  • YTHDF3 is identified as a novel hallmark of oxaliplatin resistance in CRC.
  • A molecular mechanism involving YTHDF3, eIF2AK2, and eIF3A in regulating gene translation and promoting chemo-resistance is revealed.

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