Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma

Choi, Seung‐Hyuk; Lee, Keun-Woo; Koh, Hyun Hee; Park, Su‐Jin; Yeo, So-Young; Joh, Jae‐Won; Choi, Moon Seok; Kim, Seok-Hyung; Park, Cheol Keun; Ha, Sang Yun

doi:10.1007/s00432-021-03768-3

Cited by 6 publications

(3 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Perturbation of ZMYND8 promotes initiation and progression of cancers. In fact, ZMYND8 is an antigen associated with cutaneous T-cell lymphoma [132]. In addition, chimeric transcripts of ZMYND8-v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA) were reported in a pediatric patients with acute erythroid leukemia, known as a type of AML [133].…”

Section: Reviewmentioning

confidence: 99%

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

Huang

Trivedi

et al. 2022

Discov Onc

View full text Add to dashboard Cite

Morphogenesis and organogenesis in the low organisms have been found to be modulated by a number of proteins, and one of such factor, deformed epidermal auto-regulatory factor-1 (DEAF-1) has been initially identified in Drosophila. The mammalian homologue of DEAF-1 and structurally related proteins have been identified, and they formed a family with over 20 members. The factors regulate gene expression through association with co-repressors, recognition of genomic marker, to exert histone modification by catalyze addition of some chemical groups to certain amino acid residues on histone and non-histone proteins, and degradation host proteins, so as to regulate cell cycle progression and execution of cell death. The formation of fused genes during chromosomal translocation, exemplified with myeloid transforming gene on chromosome 8 (MTG8)/eight-to-twenty one translocation (ETO) /ZMYND2, MTG receptor 1 (MTGR1)/ZMYND3, MTG on chromosome 16/MTGR2/ZMYND4 and BS69/ZMYND11 contributes to malignant transformation. Other anomaly like copy number variation (CNV) of BS69/ZMYND11 and promoter hyper methylation of BLU/ZMYND10 has been noted in malignancies. It has been reported that when fusing with Runt-related transcription factor 1 (RUNX1), the binding of MTG8/ZMYND2 with co-repressors is disturbed, and silencing of BLU/ZMYND10 abrogates its ability to inhibition of cell cycle and promotion of apoptotic death. Further characterization of the implication of ZMYND proteins in carcinogenesis would enhance understanding of the mechanisms of occurrence and early diagnosis of tumors, and effective antitumor efficacy.

show abstract

Section: Reviewmentioning

confidence: 99%

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

Huang

Trivedi

et al. 2022

Discov Onc

View full text Add to dashboard Cite

show abstract

“…(16,17) Within the realm of tumor biology, ZMYND8 has been linked to the regulation of cancer-specific programs in colorectal, prostate, breast, H3.3G34R mutant glioma, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer (NSCLC), nuclear protein in testis (NUT) carcinoma and hepatocellular carcinoma. (18)(19)(20)(21)(22)(23)(24)(25)(26) Herein, we explore resistance mechanisms reinforced by IDH1 reprogramming that allows tumor cells to survive radiotherapy. We have previously shown, mIDH1 GCCs are more resistant to radiotherapy and that inhibition of mIDH1 using AGI-5198 enhances cellular death following radiation.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Carney

Banerjee

Mujeeb

et al. 2022

Preprint

View full text Add to dashboard Cite

Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. Establishment of glioma-specific methylation patterns by mIDH1 reprogramming drives oncogenic features of cancer metabolism, stemness and therapeutic resistance. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1. Treatment of glioma cells with mIDH1 specific inhibitor AGI-5198, upregulated gene networks involved in replication stress. Specifically, we found that the expression of ZMYND8, a regulator of DNA damage response was decreased in three patient-derived glioma cell cultures (GCC) after treatment with AGI-5198. ZMYND8 functions as a chromatin reader to modulate enhancer activity and recruit DNA repair machinery. 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. The accumulation of DNA damage in ZMYND8 KO mIDH1 GCCs promoted the phosphorylation of cell cycle checkpoint proteins Chk1 and Chk2. In addition, the recruitment of ZMYND8 to sites of DNA damage has been shown to be PARP-dependent. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. Translational Relevance: Our understanding of radioresistance mechanisms in patient-derived glioma cell cultures (GCC) that endogenously express mIDH1-R132H are limited. We have uncovered a novel gene target Zinc Finger MYND-Type Containing 8 (ZMYND8) that is downregulated following treatment of human mIDH1 GCCs with mIDH1 specific inhibitors. We demonstrate that suppression of ZMYND8 expression by shRNA knockdown or genetic knockout reduces the cellular viability of mIDH1 GCCs to ionizing radiation (IR). Our findings reveal an epigenetic vulnerability of mIDH1 GCCs to ZMYND8 knockout (KO) which results in impaired resolution of IR-induced DNA damage and induction of cell cycle arrest. Additionally, ZMYND8 KO mIDH1 GCCs display increased radiosensitivity to inhibition of epigenetic regulators BRD4, HDAC, and PARP which could be mediated by enhanced replicative stress.

show abstract

Salivary protein homology between humans and dogs: Mass spectrometry-based proteomics analysis

Ahmad,

Marin,

Lowe

et al. 2024

Journal of Dentistry

View full text Add to dashboard Cite

Validation of ZMYND8 as a new treatment target in hepatocellular carcinoma

Cited by 6 publications

References 41 publications

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Salivary protein homology between humans and dogs: Mass spectrometry-based proteomics analysis

Contact Info

Product

Resources

About