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

Runping Fang, Xin Chen, Sicong Zhang, Hui Shi, Youqiong Ye, Hailing Shi, Zhongyu Zou, Peng Li, Qing Guo, Li Ma, Chuan He () and Suyun Huang ()
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Runping Fang: Virginia Commonwealth University, School of Medicine
Xin Chen: The University of Texas MD Anderson Cancer Center
Sicong Zhang: The University of Texas MD Anderson Cancer Center
Hui Shi: Virginia Commonwealth University, School of Medicine
Youqiong Ye: The University of Texas Health Science Center at Houston McGovern Medical School
Hailing Shi: The University of Chicago
Zhongyu Zou: The University of Chicago
Peng Li: Virginia Commonwealth University, School of Medicine
Qing Guo: The University of Texas MD Anderson Cancer Center
Li Ma: The University of Texas MD Anderson Cancer Center
Chuan He: The University of Chicago
Suyun Huang: Virginia Commonwealth University, School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20379-7

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