| Title: |
Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance. |
| Authors: |
Carney, Stephen V; Banerjee, Kaushik; Mujeeb, Anzar; Zhu, Brandon; Haase, Santiago; Varela, Maria L; Kadiyala, Padma; Tronrud, Claire E; Zhu, Ziwen; Mukherji, Devarshi; Gorla, Preethi; Sun, Yilun; Tagett, Rebecca; Núñez, Felipe J; Luo, Maowu; Luo, Weibo; Ljungman, Mats; Liu, Yayuan; Xia, Ziyun; Schwendeman, Anna; Qin, Tingting; Sartor, Maureen A; Costello, Joseph F; Cahill, Daniel P; Lowenstein, Pedro R; Castro, Maria G |
| Source: |
Clinical Cancer Research, vol 29, iss 9 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2023 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 3211 Oncology and Carcinogenesis (for-2020); Neurosciences (rcdc); Genetics (rcdc); Radiation Oncology (rcdc); Human Genome (rcdc); Brain Disorders (rcdc); Cancer (rcdc); Brain Cancer (rcdc); Rare Diseases (rcdc); Biotechnology (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); Cancer (hrcs-hc); Humans (mesh); Isocitrate Dehydrogenase (mesh); MYND Domains (mesh); Epigenesis; Genetic (mesh); Nuclear Proteins (mesh); Poly(ADP-ribose) Polymerase Inhibitors (mesh); Transcription Factors (mesh); Glioma (mesh); Cell Cycle Proteins (mesh); 1112 Oncology and Carcinogenesis (for); Oncology & Carcinogenesis (science-metrix); 3202 Clinical sciences (for-2020) |
| Time: |
1763 - 1782 |
| Description: |
PURPOSE: Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR). EXPERIMENTAL DESIGN: We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as a potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells and then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacologic inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP. RESULTS: Inhibition of mIDH1 leads to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response, was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 KO exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. CONCLUSIONS: These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. See related commentary by Sachdev et al., p. 1648. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt2c64b2wf; https://escholarship.org/uc/item/2c64b2wf; https://escholarship.org/content/qt2c64b2wf/qt2c64b2wf.pdf |
| DOI: |
10.1158/1078-0432.ccr-22-1896 |
| Availability: |
https://escholarship.org/uc/item/2c64b2wf; https://escholarship.org/content/qt2c64b2wf/qt2c64b2wf.pdf; https://doi.org/10.1158/1078-0432.ccr-22-1896 |
| Rights: |
public |
| Accession Number: |
edsbas.ABADBB47 |
| Database: |
BASE |