| Title: |
EZH2 Inhibition Sensitizes IDH1R132H-Mutant Gliomas to Histone Deacetylase Inhibitor |
| Authors: |
Sprinzen, Lisa; Garcia, Franklin; Mela, Angeliki; Lei, Liang; Upadhyayula, Pavan; Mahajan, Aayushi; Humala, Nelson; Manier, Lisa; Caprioli, Richard; Quiñones-Hinojosa, Alfredo; Casaccia, Patrizia; Canoll, Peter |
| Source: |
Cells, vol 13, iss 3 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
Biomedical and Clinical Sciences; Oncology and Carcinogenesis; Brain Cancer; Neurosciences; Brain Disorders; Orphan Drug; Cancer; Rare Diseases; Genetics; 2.1 Biological and endogenous factors; 6.1 Pharmaceuticals; Animals; Mice; Histone Deacetylase Inhibitors; Histones; Glioma; Benzamides; Biphenyl Compounds; Morpholines; Pyridones; EZH2; H3K27; HDAC; IDH1; OPC; gliomagenesis; Biological sciences |
| Description: |
Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
qt3820t8bm; https://escholarship.org/uc/item/3820t8bm |
| DOI: |
10.3390/cells13030219 |
| Availability: |
https://escholarship.org/uc/item/3820t8bm; https://doi.org/10.3390/cells13030219 |
| Rights: |
public |
| Accession Number: |
edsbas.F046504B |
| Database: |
BASE |