EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma

Nat Commun. 2021 Jan 8;12(1):177. doi: 10.1038/s41467-020-20379-7.

Abstract

Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. In addition, the knowledge of the disease-associated expression and function of YTHDF2 remains very limited. Here, we show that YTHDF2 overexpression clinically correlates with poor glioma patient prognosis. EGFR that is constitutively activated in the majority of GBM causes YTHDF2 overexpression through the EGFR/SRC/ERK pathway. EGFR/SRC/ERK signaling phosphorylates YTHDF2 serine39 and threonine381, thereby stabilizes YTHDF2 protein. YTHDF2 is required for GBM cell proliferation, invasion, and tumorigenesis. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, which impacts the glioma patient survival. YTHDF2 promotes tumorigenesis of GBM cells, largely through the downregulation of LXRα and HIVEP2. Furthermore, YTHDF2 inhibits LXRα-dependent cholesterol homeostasis in GBM cells. Together, our findings extend the landscape of EGFR downstream circuit, uncover the function of YTHDF2 in GBM tumorigenesis, and highlight an essential role of RNA m6A methylation in cholesterol homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic / genetics
  • Cholesterol / metabolism*
  • DNA-Binding Proteins / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioma
  • Humans
  • Liver X Receptors / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Phosphorylation
  • RNA Stability
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • DNA-Binding Proteins
  • Liver X Receptors
  • RNA-Binding Proteins
  • Transcription Factors
  • YTHDF2 protein, human
  • HIVEP2 protein, human
  • Cholesterol
  • EGFR protein, human
  • ErbB Receptors