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.
Highlights
Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood
We first queried The Cancer Genome Atlas (TCGA)[17,18], REMBRANDT19, French[20], Kawaguchi[21], and Paugh[22] datasets, and found the expression of YTHDF2, but not YTHDF1, YTHDF3, YTHDC1, or YTHDC2 correlates with poor overall survival of glioma patients in all of the datasets (Fig. 1a–c, Supplementary Fig. 1a-b)
In cultured glioma tumor cell lines and normal human astrocytes, YTHDF2 protein is highly expressed in GBM cells, especially in GBM-derived stem cells (GSCs), as compared with lower-grade glioma cells (Hs683 and SW1783) and normal human astrocytes (Fig. 1g and Supplementary Fig. 1d)
Summary
Glioblastoma (GBM) is the most common type of adult malignant brain tumor, but its molecular mechanisms are not well understood. YTHDF2 facilitates m6A-dependent mRNA decay of LXRA and HIVEP2, which impacts the glioma patient survival. The effects of EGFR activation on mRNA modification are less known. We and others have recently shown that aberrant mRNA m6A modifications actively assist the tumorigenicity of glioblastoma stem cells. EGFR mutation in GBM has been shown to increase the PI3K-dependent activation of SREBP114. We investigate m6A YTH readers in GBM, and observe a correlation between increased expression of YTHDF2 and decreased survival of glioma patients. We identify a regulatory role of EGFR activation in YTHDF2 overexpression and elucidate the underlying mechanisms in GBM cells. We uncover that YTHDF2 accelerates m6Adependent LXRA mRNA degradation, thereby promoting cholesterol dysregulation in GBM cells. YTHDF2 promotes the mRNA degradation of HIVEP2 that is critical to GBM tumorigenesis
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