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A Method for Measuring RNA N6-methyladenosine Modifications in Cells and Tissues
08:56

A Method for Measuring RNA N6-methyladenosine Modifications in Cells and Tissues

Published on: December 5, 2016

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Epitranscriptic regulation of HRAS by N6-methyladenosine drives tumor progression

Yongbo Pan1,2, Yinmin Gu3, Tihui Liu2

  • 1Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan 030032, China.

Proceedings of the National Academy of Sciences of the United States of America
|March 30, 2023
PubMed

Insights

Specific N6-methyladenosine (m6A) modifications in HRAS promote cancer progression. Targeting these m6A sites on HRAS offers a novel strategy against Ras-driven tumors.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • Ras proteins are frequently overexpressed or mutated in human cancers.
  • Mechanisms of epitranscriptic regulation of RAS in tumorigenesis are not fully understood.

Purpose of the Study:

  • To investigate the role of N6-methyladenosine (m6A) modification in RAS gene regulation during cancer development.
  • To elucidate the specific RAS isoforms and regulatory pathways involved.

Main Methods:

  • Analysis of m6A modification levels in HRAS, KRAS, and NRAS in cancer versus adjacent tissues.
  • Investigating the impact of m6A modification on H-Ras protein expression and function.
  • Identifying m6A regulators (FTO, YTHDF1/2/3) and their binding sites on HRAS mRNA.
  • Assessing the effect of targeting HRAS m6A modification on cancer cell proliferation and metastasis.
  • Correlating H-Ras, FTO, and YTHDF1 expression in clinical cancer samples.

Main Results:

  • Widespread m6A modification of HRAS, but not KRAS or NRAS, was elevated in cancer tissues.
  • m6A modification of HRAS promotes H-Ras protein expression via enhanced translational elongation.
  • Specific m6A sites in the HRAS 3' UTR, regulated by FTO and bound by YTHDF1, enhance translation.
  • Targeting HRAS m6A modification reduced cancer proliferation and metastasis.
  • Clinical data showed inverse correlation between FTO and H-Ras, and positive correlation between YTHDF1 and H-Ras.

Conclusions:

  • Specific m6A modification sites in HRAS play a crucial role in promoting cancer cell proliferation and metastasis.
  • The FTO/YTHDF1 axis regulates HRAS m6A modification to drive tumorigenesis.
  • Targeting HRAS m6A modification represents a potential therapeutic strategy for Ras-driven cancers.
Keywords:
FTOHRASYTHDF1epitranscriptomem6A

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