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ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated

Jing Ye1, Yuting Wu1, Yao Chen2

  • 1Department of Otolaryngology Head and Neck Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang `University, Hangzhou, Zhejiang, China.

Cell Death Discovery
|August 23, 2023
PubMed

Insights

AlkB homolog 5 (ALKBH5) is downregulated in hypopharyngeal squamous cell carcinoma (HPSCC), impairing cell proliferation. ALKBH5 regulates Toll-like receptor 2 (TLR2) via N6-methyladenosine (m6A) modification, offering a new therapeutic target for HPSCC.

Area of Science:

  • Molecular Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Hypopharyngeal squamous cell carcinoma (HPSCC) is highly aggressive with a poor prognosis.
  • Limited molecular studies exist for HPSCC.
  • N6-methyladenosine (m6A) RNA modification is a novel epigenetic mechanism with potential roles in HPSCC.

Purpose of the Study:

  • Investigate the role of the m6A demethylase AlkB homolog 5 (ALKBH5) in HPSCC.
  • Elucidate the mechanism by which ALKBH5 affects HPSCC cell proliferation.
  • Identify downstream targets regulated by ALKBH5 in HPSCC.

Main Methods:

  • Analysis of ALKBH5 expression in HPSCC tissues.
  • Investigation of ALKBH5's effect on HPSCC cell proliferation.
  • Assessment of Toll-like receptor 2 (TLR2) regulation by ALKBH5 in an m6A-dependent manner.
  • Identification of m6A readers (IGF2BP2, YTHDF1) involved in TLR2 regulation.

Main Results:

  • ALKBH5 expression is frequently downregulated in human HPSCC.
  • ALKBH5 impairs HPSCC cell proliferation.
  • ALKBH5 decreases TLR2 m6A modification, impacting its stability and translation via IGF2BP2 and YTHDF1.
  • This reveals a novel regulatory pathway involving ALKBH5, m6A modification, and TLR2 in HPSCC.

Conclusions:

  • ALKBH5 plays a critical role in regulating TLR2 in HPSCC through m6A demethylation.
  • The ALKBH5-TLR2 axis represents a novel mechanism in HPSCC pathogenesis.
  • Targeting ALKBH5 or m6A modification warrants further clinical investigation for HPSCC treatment.

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