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

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...

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Veröffentlicht in:Nature communications 2021-01, Vol.12 (1), p.177-17, Article 177
Hauptverfasser: Fang, Runping, Chen, Xin, Zhang, Sicong, Shi, Hui, Ye, Youqiong, Shi, Hailing, Zou, Zhongyu, Li, Peng, Guo, Qing, Ma, Li, He, Chuan, Huang, Suyun
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Sprache:eng
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Zusammenfassung: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 m 6 A-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 m 6 A methylation in cholesterol homeostasis. EGFR is frequently constitutively active in glioblastoma (GBM). Here, the authors show that EGFR induces YTHDF2 protein stabilization, which reduces cholesterol homeostasis through an RNA m6A methylation dependent molecular mechanism to promote GBM tumourigenesis.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-20379-7