Browsing by Author "Hwang, Daehee"

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    PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
    (Elsevier, 2024) Ku, Bomin; Eisenbarth, David; Baek, Seonguk; Jeong, Tae-Keun; Kang, Ju-Gyeong; Hwang, Daehee; Noh, Myung-Giun; Choi, Chan; Choi, Sungwoo; Seol, Taejun; Kim, Yun-Hee; Woo, Sang Myung; Kong, Sun-Young; Lim, Dae-Sik; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
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    Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
    (Frontiers, 2019-05-07) Min, Byong-Keol; Park, Sungmi; Kang, Hyeon-Ji; Kim, Dong Wook; Ham, Hye Jin; Ha, Chae-Myeong; Choi, Byung-Jun; Lee, Jung Yi; Oh, Chang Joo; Yoo, Eun Kyung; Kim, Hui Eon; Kim, Byung-Gyu; Jeon, Jae-Han; Hyeon, Do Young; Hwang, Daehee; Kim, Yong-Hoon; Lee, Chul-Ho; Lee, Taeho; Kim, Jung-whan; Choi, Yeon-Kyung; Park, Keun-Gyu; Chawla, Ajay; Lee, Jongsoon; Harris, Robert A.; Lee, In-Kyu; Biochemistry and Molecular Biology, School of Medicine
    Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.