Summary: Study shows how cholesterol becomes dysregulated in brain cancer cells and reports the gene responsible for the dysregulation could be a potential target to help treat glioblastoma brain cancer.
Source: Virginia Commonwealth University
Most people relate cholesterol to heart health, but it is also a critical component in the growth and spread of brain cancer. VCU Massey Cancer Center researcher Suyun Huang, Ph.D., recently discovered how cholesterol becomes dysregulated in brain cancer cells and showed that the gene responsible for it could be a target for future drugs.
The mean survival of patients with the most common and aggressive type of brain cancer, glioblastoma multiforme (GBM), is 14 months. The need to find new, effective treatments is urgent and has driven Huang, a member of the Cancer Biology research program at Massey, to detail the workings of numerous genes, proteins, enzymes and other cellular components that contribute to brain cancer growth. Her studies are revealing a biological “roadmap” showing previously unknown functions of genes.
Huang’s most recent study, published in the journal Nature Communications, pinpoints a gene called YTHDF2 as a crucial link in a chain leading to the development and growth of GBM. It works through a process set in motion by another gene with a well-established reputation for driving cancer progression, EGFR.
“These findings are exciting because we can potentially target YTHDF2 expression by using YTHDF2 small molecule inhibitors to control glioblastoma tumor growth and spread,” says Huang, who is also a professor in the Department of Human and Molecular Genetics at VCU School of Medicine. “Our experiments also showed that we can stop the formation and growth of brain cancer cells by blocking YTHDF2 expression, so it could also be a powerful target for drug development.”
EGFR is frequently overactivated in many aggressive cancers, including GBM. Huang’s team found that EGFR drives the overexpression of TYHDF2, which then sustains increased cholesterol levels for the invasive growth and development of GBM cells through a process that degrades the LXRα and HIVEP2 genes. LXRα is known to regulate cholesterol levels within cells and HIVEP2 is involved in the development of brain tissue.
Huang’s study is the first to describe this cell signaling cascade, and it helps fill in important parts of the “roadmap” leading to GBM. It is also the first study to show that N6-methyladenosine (m6A), a DNA modification found in nearly all cell-based life forms, plays a role in brain tumor growth and cholesterol metabolism. Huang’s team found that the increase in YTHDF2 expression caused m6A modifications in the mRNA of LXRα and HIVEP2, which inhibited their functions.
Next, Huang and her collaborators plan to evaluate different YTHDF2 inhibitors and establish their effects in lab and animal models.
“EGFR inhibition and cholesterol regulation are both promising strategies for GBM treatment,” says Huang. “Our study offers an exciting new approach that could potentially work hand-in-hand with these strategies to regulate and treat GBM.”
Additional researchers involved in this study include Runping Fang, Ph.D., and Peng Li, M.D., both from the Department of Human and Molecular Genetics at VCU School of Medicine; Xin Chen, Ph.D., Sicong Zhang, Ph.D., Qing Guo, Ph.D., and Li Ma, Ph.D., all from MD Anderson Cancer Center; Youqiong Ye, Ph.D., from the University of Texas Health Science Center; and Zhongyu Zou, Ph.D., Chuan He, Ph.D., and Hailing Shi, Ph.D., all from the University of Chicago.
About this brain cancer research news
Source: Virginia Commonwealth University
Contact: John Wallace – Virginia Commonwealth University
Image: The image is in the public domain
Original Research: Open access.
“EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma” by Runping Fang, Xin Chen, Sicong Zhang, Hui Shi, Youqiong Ye, Hailing Shi, Zhongyu Zou, Peng Li, Qing Guo, Li Ma, Chuan He & Suyun Huang. Nature Communications
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 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.