https://scholar.dgist.ac.kr/handle/20.500.11750/16013 2026-05-15T00:32:57Z 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 https://scholar.dgist.ac.kr/handle/20.500.11750/57239 Title: Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma Author(s): Mbah, Nneka E.; Myers, Amy L.; Sajjakulnukit, Peter; Chung, Chan; Thompson, Joyce K.; Hong, Hanna S.; Giza, Heather; Dang, Derek; Nwosu, Zeribe C.; Shan, Mengrou; Sweha, Stefan R.; Maydan, Daniella D.; Chen, Brandon; Zhang, Li; Magnuson, Brian; Zhu, Zirui; Radyk, Megan; Lavoie, Brooke; Yadav, Viveka Nand; Koo, Imhoi; Patterson, Andrew D.; Wahl, Daniel R.; Franchi, Luigi; Agnihotri, Sameer; Koschmann, Carl J.; Venneti, Sriram; Lyssiotis, Costas A. Abstract: H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain. © The Author(s) 2024. 2024-09-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/47761 Title: Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways Author(s): Venneti, Sriram; Kawakibi, Abed Rahman; Ji, Sunjong; Waszak, Sebastian M.; Sweha, Stefan R.; Mota, Mateus; Pun, Matthew; Deogharkar, Akash; Chung, Chan; Tarapore, Rohinton S.; Ramage, Samuel; Chi, Andrew; Wen, Patrick Y.; Arrillaga-Romany, Isabel; Batchelor, Tracy T.; Butowski, Nicholas A.; Sumrall, Ashley; Shonka, Nicole; Harrison, Rebecca A.; de Groot, John; Mehta, Minesh; Hall, Matthew D.; Daghistani, Doured; Cloughesy, Timothy F.; Ellingson, Benjamin M.; Beccaria, Kevin; Varlet, Pascale; Kim, Michelle M.; Umemura, Yoshie; Garton, Hugh; Franson, Andrea; Schwartz, Jonathan; Jain, Rajan; Kachman, Maureen; Baum, Heidi; Burant, Charles F.; Mottl, Sophie L.; Cartaxo, Rodrigo T.; John, Vishal; Messinger, Dana; Qin, Tingting; Peterson, Erik; Sajjakulnukit, Peter; Ravi, Karthik; Waugh, Alyssa; Walling, Dustin; Ding, Yujie; Xia, Ziyun; Schwendeman, Anna; Hawes, Debra; Yang, Fusheng; Judkins, Alexander R.; Wahl, Daniel; Lyssiotis, Costas A.; de la Nava, Daniel; Alonso, Marta M.; Eze, Augustine; Spitzer, Jasper; Schmidt, Susanne V.; Duchatel, Ryan J.; Dun, Matthew D.; Cain, Jason E.; Jiang, Li; Stopka, Sylwia A.; Baquer, Gerard; Regan, Michael S.; Filbin, Mariella G.; Agar, Nathalie Y. R.; Zhao, Lili; Kumar-Sinha, Chandan; Mody, Rajen; Chinnaiyan, Arul; Kurokawa, Ryo; Pratt, Drew; Yadav, Viveka N.; Grill, Jacques; Kline, Cassie; Mueller, Sabine; Resnick, Adam; Nazarian, Javad; Allen, Joshua E.; Odia, Yazmin; Gardner, Sharon L.; Koschmann, Carl Abstract: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. © 2023 The Authors; Published by the American Association for Cancer Research. 2023-10-31T15:00:00Z