Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Abstract

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 potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacological inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP. Results: Inhibition of mIDH1 lead 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 knockout (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.

ZMYND8 protects breast cancer stem cells against oxidative stress and ferroptosis through activation of NRF2

“…Hyperactivation of NRF2 is also associated with several types of therapy resistance in cancer, including chemoresistance, radioresistance, targeted therapy resistance, and immunotherapy resistance (10,(34)(35)(36). Given that ZMYND8 has been shown to promote radioresistance in glioma (37), it would be interesting to study whether ZMYND8-mediated NRF2 activation in BCSCs could promote resistance to therapies in breast cancer.…”

Bacteria associated with glioma: a next wave in cancer treatment

“…Consistent with the findings of glioma malignancy, research has shown a clear correlation between the glioma IDH-mutant and the genera Bergeyella and Capnocytophaga. The IDH1-mutant is crucial for the induction of glucose, the metabolism of glutamine, the creation of lipids, and the control of cellular redox homeostasis in glioma cells ( Carney et al., 2023 ). Their study showed that IDH-mutant people had a significantly higher enrichment of oral microbial gene functions related to lipid metabolism and the AMPK signaling pathway.…”

Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation

“…IDH1 R132H is associated with a better prognosis in gliomas (4,7,8) and impacts multiple cellular functions, including cell differentiation (9), invasion (10), immune response (11)(12)(13), and responses to cellular stress and DNA-damage (14)(15)(16). We, and others, recently demonstrated that the epigenetic reprogramming in mIDH1 results in enhanced DNAdamage responses and impaired response to radiotherapy (15)(16)(17)(18). Furthermore, mIDH1 was shown to elicit a cellular metabolic reprogramming that could modify the energetic state of mIDH1 glioma cells and the tumor microenvironment (TME) (16,(19)(20)(21)(22).…”