https://scholar.dgist.ac.kr/handle/20.500.11750/16013 2026-06-04T02:05:48Z https://scholar.dgist.ac.kr/handle/20.500.11750/60370 Title: Integrated transcriptomic analysis reveals KRAS-associated gene activation and epigenetic regulation in mutant IDH1 glioma Author(s): Jeon, Jinha; Park, Jiyoon; Gim, Sujeong; Chung, Chan Abstract: Background Mutations in isocitrate dehydrogenase 1 (IDH1) are hallmark features of diffuse gliomas and drive extensive metabolic and epigenetic reprogramming through accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). However, the downstream transcriptional programs and chromatin-based mechanisms linking mutant IDH1 to oncogenic signaling remain incompletely understood. Objective This study aimed to define transcriptional changes associated with the IDH1 R132H mutation and to determine how epigenetic mechanisms influence KRAS-associated gene expression. Methods We analyzed transcriptomic data from the TCGA-LGG cohort and public RNA-seq datasets to identify differentially expressed genes and enriched pathways. Key findings were validated using qRT-PCR in cellular models expressing IDH1 R132H. To assess epigenetic regulation, we performed knockdown experiments targeting the H3K36 methyltransferases SETD2 and SMYD5. Results Integrated transcriptomic analyses revealed consistent enrichment of KRAS signaling-related gene signatures in IDH1 R132H tumors and cell models. qRT-PCR validation confirmed altered expression of key KRAS-associated genes involved in immune response, extracellular matrix remodeling, and tumor-related processes. Notably, the knockdown of SETD2 or SMYD5 significantly reduced the expression of these genes, indicating that H3K36 methylation-associated chromatin regulation contributes to their transcriptional activation. Conclusion These findings demonstrate that mutant IDH1 promotes KRAS-associated transcriptional programs, at least in part, through epigenetic mechanisms involving H3K36 methylation-dependent chromatin regulation in glioma. https://scholar.dgist.ac.kr/handle/20.500.11750/60369 Title: In Silico Prediction of EZHIP Post-Translational Modification Sites and Small-Molecule High-Throughput Screening for Quantitative EZHIP Modulation Author(s): Moon, Jimin; Hwang, Jiwon; Chung, Chan Abstract: Background Posterior fossa group A (PFA) ependymoma is a lethal pediatric brain tumor driven predominantly by epigenetic dysregulation. Enhancer of Zeste Homologs Inhibitory Protein (EZHIP) is a defining oncogenic factor in PFA ependymoma that inhibits PRC2 activity, inducing a global loss of H3K27me3 and sustaining aberrant developmental transcriptional programs. Although the metabolic modulator, metformin, reduces EZHIP protein levels, the mechanisms governing EZHIP regulation remain undefined. Methods We generated a stable HEK293T reporter cell expressing HA-and RFP-tagged EZHIP together with a GFP viability control, enabling quantitative and viability-normalized assessment of EZHIP abundance. In silico post-translational modification prediction was performed using Phos-phoSitePlus and NetPhos 3.1 to identify candidate regulatory residues and upstream kinases. A focused panel of pathway targeting compounds was evaluated using fluorescence-based high-through-put screening, followed by secondary validation including cell counting, LC50 (half-maximal lethal concentration) analysis, and Western blotting. Results Computational analyses identified multiple high-confidence serine phosphorylation sites on EZHIP and implicated AMPK, MAPK, PKC, AKT, and CK2 signaling pathways. High-through-put screening revealed that activation of the AMPK axis robustly suppressed EZHIP protein levels. Secondary validation demonstrated that biguanides activating AMPK reduced EZHIP abundance independently of cytotoxicity and restored global H3K27me3 levels. In contrast, PKC activation increased EZHIP protein abundance. Conclusion Our study identifies EZHIP as a dynamically regulated oncoprotein controlled by post-translational signaling pathways. AMPK and PKC exert opposing effects on EZHIP stability, defining actionable regulatory mechanisms for therapeutic targeting in EZHIP-driven cancers. © 2026 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology. 2026-03-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/60354 Title: Histone mark remodeling in cancer: an enhancer-centered perspective Author(s): Park, Jiyoon; Jeon, Jinha; Gim, Sujeong; Chung, Chan Abstract: Epigenetic deregulation is a defining feature of cancer, and histone modification remodeling plays a central role in reshaping malignant transcriptional programs. Histone marks collectively organize chromatin states that govern enhancer activity, promoter competence, and stability of repressive domains. Across diverse tumor types, redistribution of active and repressive histone modifications reconfigures regulatory landscapes that sustain oncogenic amplification, lineage plasticity, and adaptive resistance. In this review, we examine histone mark remodeling in cancer through an enhancer-centered perspective. We discuss how the gain of H3K27ac-marked enhancers, super-enhancer formation, the erosion of lineage-restrictive regulatory elements, and the redistribution of repressive marks cooperate to reorganize transcriptional circuitry. We further outline the convergent mechanisms driving these alterations, including mutations in chromatin regulators, signal-dependent modulation of epigenetic enzymes, metabolic influences on chromatin state, and changes in three-dimensional genome architecture. The functional consequences of histone mark reprogramming, ranging from cell state transitions and tumor heterogeneity to transcriptional dependency and therapy-associated chromatin adaptation, are considered in the context of tumor evolution. Finally, we highlight emerging single-cell, spatial, and integrative multi-omics approaches that enable systems-level interpretation of chromatin landscapes and identification of context-specific vulnerabilities. By framing histone modification dynamics in terms of enhancer reconfiguration, this review provides a mechanistic and translational perspective on how chromatin remodeling sustains malignant identity and offers opportunities for therapeutic intervention. https://scholar.dgist.ac.kr/handle/20.500.11750/60063 Title: Lactate metabolism in H3K27M mutant diffuse midline gliomas Author(s): Lum, Joanna; Deogharkar, Akash; Chung, Chan; Sajjakulnukit, Peter; Lyssiotis, Costas; Venneti, Sriram Abstract: Metabolic reprogramming driven by oncogenes is a cancer hallmark that enables tumor cells to consume nutrients in vast quantities to support their unchecked proliferation. Our laboratory has shown that the H3K27M mutation in Diffuse Midline Glioma (DMG), driven by the Warburg effect, enhances glycolysis and promotes lactate production. Historically/conventionally, lactate was thought to be a metabolic waste product. However, recent studies have challenged this notion by demonstrating numerous biological roles for lactate in various disease settings. This includes the acidification of the tumor microenvironment, immune suppression, and a fuel for mitochondrial energy production. These discoveries have prompted our efforts to investigate the role of lactate metabolism in DMG. Despite its recognized roles in other cancer types, lactate’s contribution to DMG biology is not well characterized. This study explores its energetic utilization by DMG cells. Using liquid chromatography/mass spectrometry (LC/MS) in isogenic mouse neuronal stem cells, we find that H3K27M, compared to H3 WT cells, have elevated intracellular lactate levels. Furthermore, patient-derived DMG cells utilize lactate as an energy source in nutrient-depleted conditions. Notably, genetic and pharmacologic inhibition of lactate dehydrogenase (LDHA & LDHB) hinders cell growth. These findings suggest that lactate metabolism plays a critical role in the physiology of DMG cells and warrant further investigation into its potential role in driving DMG cancer progression. 2025-11-18T15:00:00Z