EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. (Nat Commun. 2021, 12:177)

報告日期: 2021/03/26
報告時間: 15:10/16:00
報告學生: 何冠達
講評老師: 林世杰
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EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma

Fang, R., Chen, X., Zhang, S. et al.  Nat Commun 12, 177 (2021)

Speaker : Kuan-Ta Ho 何冠達                                               Time : 03/26/2021, 03:10 PM

Commentator : Dr. Shih-Chieh Lin 林世杰老師               Room : 602, college of medicine

ABSTRACT

Glioblastoma (GBM, WHO grade IV glioma) is the most common and the most malignant brain tumor in adults. According to TCGA-GBM dataset, EGFR amplification (~50% of GBM) and/or mutation is the main characteristic of GBM[1]. N6-methyladenosine (m6A) is the most frequent RNA modification in mammalian eukaryotic cells and can be regulated by “writers”(N6-adenosine methylation), “erasers”(N6-methyladenosine demethylation), and “readers”(N6-metyladenosine recognition) [2]. It has been reported that N6-methyladenosine (m6A) RNA modification by METTL3/METTL14(writers) or FTO/ALKBH5(erasers) could regulate self-renewal and tumorigenicity of glioblastoma stem-like cells (GSCs)[3]. However, it still remained unclear that how EGFR may regulate RNA modifications in GBM. In this study, they focused on the YTH family (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2), a group of the m6A readers that were rarely discussed in m6A modification of GBM. TCGA-LGG&GBM dataset significantly indicated that only YTHDF2 expression negatively correlated with the prognosis of GBM among YTH family. Moreover, they suggested that YTHDF2 stabilization may promote mRNA degradation of LXRA and HIVEP2 through the phosphorylation of EGFR/SRC/ERK at S39 and T381 to inhibit cholesterol efflux and support proliferation and invasion in GBM.       In conclusion, this study may explain the mechanism of dysregulated cholesterol homeostasis and highlighted the role of EGFR in regulating m6A RNA modification by reader YTHDF2 in GBM. 

REFERENCES

  1. Brennan, C.W., et al., The somatic genomic landscape of glioblastoma. Cell, 2013. 155(2): p. 462-77.
  2. Yang, C., et al., The role of m(6)A modification in physiology and disease. Cell Death Dis, 2020. 11(11): p. 960.
  3. Cui, Q., et al., m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep, 2017. 18(11): p. 2622-2634.