Issue No. 37, March 2021
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine, VCU and external experts focusing on important medically-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
EGFR-YTHDF2-cholesterol Axis Promotes Invasive Growth of Glioblastoma

A recent study published in Nature Communications from Dr. Huang and colleagues demonstrates that EGFR signaling stabilizes YTHDF2, a N6-methyladenosine (m6A) reader, in glioblastoma is important for cholesterol dysregulation and invasive growth of glioblastoma, and is a potential target for therapeutic intervention for life-threatening glioblastoma.

  • Public datasets analyses revealed YTHDF2 expression is increased in glioblastoma and is negatively correlated with overall survival in glioma patients.

  • YTHDF2 is indispensable for the growth and invasion of glioblastoma stem cells. Its depletion impairs invasive tumor formation and prolongs mice survival.

  • EGFR/SRC/ERK1/2 prevent YTHDF2 protein from degradation through directly phosphorylating YTHDF2.

  • Using RNA immunoprecipitation sequencing (RIP-seq), RNA-seq and m6A methylome profiling, combined with public datasets and references analysis, LXRA and HIVEP2 were identified as functionally essential targets of YTHDF2.

  • YTHDF2 promoted the mRNA decay of liver X receptors (LXRs) and human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) in glioblastoma dependent on the recognition of YTHDF2 to m6A-modified mRNA.

  • YTHDF2-promoted mRNA decay of LXRA and HIVEP2 inhibits their expression and leads to cholesterol dysregulation and invasive growth of glioblastoma stem cells.

Glioblastomas (GBM) are a devastating type of brain tumor, with a median survival of 14 months, regardless of treatment. The tumor cells that invade adjacent brain tissue and contribute to the intracranial dissemination of GBM, represent a major clinical problem. The most prevailing genetic alterations are the amplification and mutation of EGFR that occur in more than 50% of GBMs. EGFR signaling has been reported to confer global effects on the modulation of multiple pathways in GBM. New research from Dr. Huang and colleagues published in Nature Communications* uncovers the EGFR signaling-mediated stabilization of YTHDF2 resulted in low expression of LXRA and HIVEP2 and leads to cholesterol dysregulation and invasive growth of glioblastoma.

The results from the study* indicate that YTHDF2, a m6A reader, is increased in glioblastoma and correlated with decreased overall survival in glioblastoma patients. To investigate the molecular mechanisms of YTHDF2 function in glioblastoma, RNA-sequencing, RNA immunoprecipitation sequencing (RIP-seq) and m6A methylome profiling were used to find the downstream targets of YTHDF2 (Figure 1, left). The downregulation of LXRA and HIVEP2 induced by YTHDF2 is dependent on the recognition by YTHDF2 of m6A-modified mRNA and mRNA decay in glioblastoma (Figure 1, right). The study uncovers that YTHDF2 upregulation is vital for cholesterol dysregulation and invasive growth of glioblastoma and YTHDF2 could be a novel therapeutic target for life-threatening glioblastoma.
Figure 1: Left: Schematic workflow of YTHDF2 downstream targets analysis. Right: EGFR signaling promotes the stability of YTHDF2 leading to mRNA decay of LXRA and HIVEP2 which are responsible for cholesterol dysregulation and invasive growth of glioblastoma cells.
Dr. Runping Fang, a scientist in Human and Molecular Genetics at Virginia Commonwealth University, School of Medicine is the first author of this paper and performed much of the biological and animal work. The present study was supported in part by federal grants RM1 HG008935, and 1R01CA198090, and by Paul M. Corman, MD Chair in Cancer Research endowment fund to Suyun Huang.
 
Publications:
*Fang R, Chen X, Zhang S, Shi H, Ye Y, Shi H, Zou Z, Li P, Guo Q, Ma L, He C and Huang S. EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. Nature Communications 2021 Jan 8;12(1):177. PMCID: PMC7794382
 
About the Investigators: Suyun Huang, MD, PhD, is Professor of Human and Molecular Genetics (HMG), member of the VCU Institute of Molecular Medicine (VIMM) and Paul M. Corman, MD Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Chuan He, PhD, is Professor of Department of Chemistry and Institute for Biophysical Dynamic, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biology, University of Chicago. Runping Fang, Hui Shi and Peng Li are scientists in HMG. Sicong Zhang, Xin Chen, Qing Guo, and Li Ma are from the University of Texas MD Anderson Cancer Center. Youqiong Ye is from the Department of Biochemistry and Molecular Biology, at the University of Texas Health Science Center, Houston McGroven Medical School. Hailing Shi and Zhongyu Zou are from Department of Chemistry and Institute for Biophysical Dynamic and Department of Biochemistry and Molecular Biology, University of Chicago.