YTHDC2 inhibits HPV-positive cervical cancer growth by suppressing SLC7A11 in a ferroptosis-dependent manner

Li Ren1, Junjun Zhang1, Jinjin Yang1

  • 1Department of Gynecology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.

Oncology Letters
|September 8, 2025
PubMed

Insights

Low levels of YTHDC2 promote cervical cancer (CC) growth by enhancing protein synthesis of SLC7A11, inhibiting ferroptosis in human papillomavirus (HPV)-positive CC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • High-risk human papillomavirus (HPV) infection is a primary cause of cervical cancer (CC).
  • YTH N6-methyladenosine RNA-binding protein C2 (YTHDC2) is an RNA-binding protein implicated in various cancers, but its role in CC is unclear.
  • Understanding YTHDC2's function in HPV-positive CC is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of YTHDC2 in HPV-positive cervical cancer cell proliferation and ferroptosis.
  • To elucidate the molecular mechanisms underlying YTHDC2's function, particularly its regulation of protein synthesis.
  • To determine the relationship between YTHDC2, solute carrier family 7 member 11 (SLC7A11), and ferroptosis in CC.

Main Methods:

  • Comparative analysis of YTHDC2 expression in HPV-positive versus HPV-negative CC samples and cell lines.
  • Cell viability and proliferation assays (Cell Counting Kit-8, colony formation) following YTHDC2 overexpression or silencing.
  • Assessment of ferroptosis markers (apoptosis, reactive oxygen species, SLC7A11 levels).
  • Bioluminescent assays using luciferase constructs to analyze SLC7A11 5'-untranslated region (UTR) activity and YTHDC2's effect on translation initiation.

Main Results:

  • YTHDC2 expression was significantly reduced in HPV-positive CC samples and cell lines.
  • YTHDC2 overexpression inhibited CC cell viability and proliferation, while silencing YTHDC2 enhanced these processes.
  • Overexpression of YTHDC2 induced ferroptosis characteristics and reduced SLC7A11 translation via its 5'-UTR.
  • Increased SLC7A11 levels partially reversed the effects of YTHDC2 on proliferation and ferroptosis.

Conclusions:

  • Reduced YTHDC2 expression in HPV-positive CC promotes cancer cell proliferation and inhibits ferroptosis.
  • YTHDC2 regulates CC progression by controlling SLC7A11 translation initiation.
  • Targeting YTHDC2 or modulating SLC7A11 levels may offer therapeutic strategies for HPV-positive cervical cancer.

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