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METTL1 coordinates cutaneous squamous cell carcinoma progression via the m7G modification of the ATF4 mRNA

Xinru Zhang1, Tong Chen1, Fanrong Zhang1

  • 1School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.

Cell Death Discovery
|January 27, 2025
PubMed

Insights

Methyltransferase-like 1 (METTL1) fuels cutaneous squamous cell carcinoma (cSCC) by modifying ATF4 mRNA. Inhibiting METTL1 suppressed cSCC growth, highlighting METTL1 as a potential therapeutic target for this cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • N7-methylguanosine (m7G) modification, catalyzed by Methyltransferase-like 1 (METTL1), is prevalent in RNA and implicated in various cancers.
  • The specific role of METTL1-mediated m7G modification in cutaneous squamous cell carcinoma (cSCC) remains largely unelucidated.

Purpose of the Study:

  • To investigate the role and mechanism of METTL1-mediated m7G modification in the development of cutaneous squamous cell carcinoma (cSCC).
  • To explore METTL1 as a potential therapeutic target for cSCC.

Main Methods:

  • Quantification of METTL1 levels in cSCC tumors and cell lines.
  • Assessment of cSCC cell behavior (survival, migration, invasion) and xenograft tumor growth following METTL1 inhibition.
  • RNA sequencing, m7G-specific immunoprecipitation (MeRIP)-qPCR, and mRNA stability assays to identify METTL1 targets and mechanisms.
  • Analysis of the association between METTL1 and ATF4 expression in cSCC tumors.
  • Evaluation of ATF4's role in cSCC glycolysis and response to METTL1 inhibition.

Main Results:

  • METTL1 levels were significantly elevated in cSCC tumors and cell lines.
  • METTL1 inhibition reduced cSCC cell survival, migration, invasion, and xenograft tumor growth.
  • METTL1 specifically m7G-modified ATF4 mRNA, enhancing its expression via increased stability.
  • METTL1's methyltransferase activity was crucial for ATF4 mRNA modification.
  • ATF4 expression positively correlated with METTL1 levels in cSCC.
  • Restoring ATF4 expression in cSCC cells promoted glycolysis and counteracted METTL1 knockdown's anti-tumor effects.

Conclusions:

  • METTL1 and its m7G modification play a critical role in promoting cSCC tumorigenesis, partly through the upregulation of ATF4.
  • The METTL1-ATF4 axis represents a promising therapeutic target for cutaneous squamous cell carcinoma.

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