Gliomas presently remain incurable with currently available radiation and chemotherapeutic modalities. Intensive molecular characterization of gliomas have revealed a rich molecular diversity of aberrations that give rise to the hope that we can significantly impact this disease through translation of the most promising targets into personalized therapies. This proposal directly addresses this need by investigating the tumor suppressive mechanism of a novel target, miR-148a, identified using an innovative and powerful DNA methylation profiling strategy established in the PI's laboratory. Although not yet studied in glioma, miRNA-148a is emerging as a tumor suppressive miRNA in other cancers. As small non-coding RNAs that suppress gene expression, miRNAs occupy key roles in cancer mechanisms and provide emerging therapeutic targets as either themselves or genes they regulate. Extensive genomic characterization of cancer tissue has revealed the widespread presence of aberrant DNA CpG island methylation, which can be associated with the epigenetic silencing of some miRNAs. The recently discovered isocitrate dehydrogenase (IDH) mutation is thought not only to provide a biomarker of secondary gliomas but also represent an initiating event in gliomagenesis. Our research in IDHMUT gliomas has contributed to the recognition of an IDHMUT-associated genome-wide hypermethylation profile, glioma-CpG island methylator phenotype (G-CIMP), that is not found in normal tissue or IDH wild-type gliomas. This has led to a widely accepted but as yet unsupported hypothesis that G-CIMP occupies a pivotal role in gliomagenesis through silencing of tumor suppressive genes and/or genes involved in differentiation. Thus, we hypothesized that IDHMUT-associated DNA hypermethylation may silence the expression of important tumor-suppressive miRNAs in glioma. As shown in our preliminary data, we used unbiased methylation profiling to identify hypermethylated miRNA genes in the context of G-CIMP, and among these candidates, miRNA-148a appears not only to have tumor suppressive properties but also to directly regulate DNMT1, a key gene involved in DNA methylation maintenance. In this proposal, we test the central hypotheses that IDHMUT causes epigenetic silencing of the tumor suppressive miR-148a and that re-expression of miR-148a provides a novel strategy for glioma treatment, particularly for the IDHMUT subset. To do so, the aims are: 1) to investigate the molecular basis linking IDH mutation and miR148a downregulation, 2) to establish miR-148a downstream target genes contributing to tumor suppression, and 3) to explore the therapeutic potential of miR-148a in IDHMUT glioma.
These aims will be accomplished combining an unbiased high-resolution methylation profiling technique, extensive patient tissue resources, and a variety of cell models including patient-derived glioma neurospheres cells. Accomplishment of the stated aims will have a significant contribution towards the development of novel tailored treatments for gliomas based on restoration of deficient miRNAs.

Public Health Relevance

to Public Health Consistent with the mission of the NIH, the proposed research is aimed at directly improving outcomes for adult patients diagnosed with diffuse gliomas. As the most common malignant primary brain cancer in adults, affecting 20,000 people yearly in the US, diffuse gliomas remain devastating and incurable. This proposal focuses on the therapeutic implications of restoring a critical tumor suppressive miRNA that we found to be deficient in a large fraction of gliomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ganguly, Aniruddha
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Li, Tie; Cox, Christopher D; Ozer, Byram H et al. (2018) D-2-Hydroxyglutarate Is Necessary and Sufficient for Isocitrate Dehydrogenase 1 Mutant-Induced MIR148A Promoter Methylation. Mol Cancer Res 16:947-960
Nguyen, HuyTram N; Lie, Amy; Li, Tie et al. (2017) Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy. Neuro Oncol 19:394-404
Laks, Dan R; Crisman, Thomas J; Shih, Michelle Y S et al. (2016) Large-scale assessment of the gliomasphere model system. Neuro Oncol 18:1367-78
Panosyan, Eduard H; Lasky, Joseph L; Lin, Henry J et al. (2016) Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids. J Neurooncol 128:57-66
Yong, William H; Shabihkhani, Maryam; Telesca, Donatello et al. (2015) Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients. PLoS One 10:e0141334
Fu, Xudong; Chin, Randall M; Vergnes, Laurent et al. (2015) 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab 22:508-15
Tso, Jonathan L; Yang, Shuai; Menjivar, Jimmy C et al. (2015) Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide. Mol Cancer 14:189
Rapkins, Robert W; Wang, Fan; Nguyen, HuyTram N et al. (2015) The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide. Neuro Oncol 17:1589-98
Li, Sichen; Chowdhury, Reshmi; Liu, Fei et al. (2014) Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas. Clin Cancer Res 20:5808-22