https://scholar.dgist.ac.kr/handle/20.500.11750/289 2026-04-24T18:39:39Z https://scholar.dgist.ac.kr/handle/20.500.11750/60202 Title: Cereblon (CRBN) inhibits prostate cancer metastasis by negatively regulating 6-phosphogluconate dehydrogenase (6PGD) Author(s): Guchhait, Koushik; Yoon, Hyeon-Seung; An, Hyun-Su; Shin, Seungheon; Nam, Hye Seung; Yanqui-Rivera, Francisco D.; Ona, Samara M.; Mendez, Miguel A.; Hwang, Jong Yeon; Park, Daeho; Park, Chul-Seung; Han, Jee-Young; Chung, Doo Yong; Park, Seokjae; Kim, Eun-Kyoung; Yang, Su-Geun; Cho, Steve K. Abstract: Metastasis is the primary cause of mortality in advanced prostate cancer, and the emergence of resistance to androgen receptor (AR)-targeted therapies highlights the urgent need for alternative therapeutic strategies. Metabolic reprogramming has increasingly been recognized as a key driver of metastatic progression. In this study, we uncover a novel tumor-suppressive role for cereblon (CRBN), a substrate receptor of the CRL4CRBN E3 ubiquitin ligase complex, in modulating prostate cancer metastasis through regulation of 6-phosphogluconate dehydrogenase (6PGD), a critical enzyme in the oxidative pentose phosphate pathway (oxPPP). CRBN directly binds a conserved C-terminal alpha-helix in 6PGD, promoting its polyubiquitination and proteasomal degradation independently of immunomodulatory drugs (IMiDs). Genetic or pharmacological loss of CRBN via CRISPR/Cas9, RNA interference, or PROTAC-mediated degradation stabilized 6PGD and elevated the NADPH/NADP+ ratio. Conversely, re-expression of wild-type CRBN reduced 6PGD levels, restored NADPH/NADP+ ratio, and suppressed cell migration and invasion. Transcriptomic profiling revealed CRBN-induced upregulation of CDH1 and downregulation of the EMT marker MMP1, while CRBN degradation produced the opposite pattern-both effects were reversed by 6PGD inhibition. These regulatory effects were conserved across multiple cancer cell lines and observed in CRBN-deficient mouse tissues. Functional studies using intra-splenic xenograft models further demonstrated that CRBN suppresses metastatic dissemination. Collectively, our findings identify 6PGD as a novel endogenous substrate of CRBN and establish the CRBN-6PGD axis as a critical metabolic checkpoint in prostate cancer metastasis. Therapeutic targeting of this pathway may offer promising strategies for CRBN-deficient or 6PGD-driven cancers. 2026-02-28T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/59920 Title: Threonic acid, an ascorbic acid metabolite, synergizes with intermittent fasting to ameliorate obesity Author(s): Oh, Sungjoon; Park, Seokjae; Kim, Eun-Kyoung Abstract: Intermittent fasting (IF) is a safe and sustainable approach for obesity treatment, yet its weight loss efficacy is relatively modest compared with that of pharmacologic anti-obesity therapies. The synergistic benefits of pairing IF with administration of nutrient-derived metabolites remain poorly understood. Here we report that combining IF with threonic acid (TA), an ascorbic acid metabolite, led to more pronounced reductions in body weight and food intake, as well as improvements in energy expenditure and glycemic control, compared with either intervention alone in diet-induced obese mice. These metabolic benefits were associated with the anorexigenic role of TA in reversing fasting-induced upregulation of the hypothalamic orexigenic neuropeptides NPY and AGRP. In the hypothalamus, TA competed with glucose for uptake via glucose transporter 3 (GLUT3), while IF boosted the TA uptake through both glucose depletion and upregulation of GLUT3, resulting in a more robust suppression of NPY and AGRP expression. Collectively, our findings highlight the combination of TA with IF as a promising metabolite-based combinatorial strategy to enhance the therapeutic efficacy of obesity treatment. 2025-12-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/58519 Title: ATP stimulates appetite by enhancing the expression of hypothalamic orexigenic neuropeptides Author(s): Kim, Nayoun; Kim, Eun-Kyoung Abstract: Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control. © The Author(s) 2025. 2025-05-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/58446 Title: Adenosine transmission from hypothalamic tanycytes to AGRP/NPY neurons regulates energy homeostasis Author(s): Kim, Nayoun; Kim, Seolsong; Park, Seokjae; Kim, Eun-Kyoung Abstract: Tanycytes are a pivotal component of the hypothalamic network that controls energy homeostasis. Despite their importance, the regulatory mechanisms governing tanycyte–neuron interactions in response to metabolic signals remain unexplored. Here we report that adenosine signaling between tanycytes and AGRP/NPY neurons is crucial for tanycytic metabolic regulation mediated by translocator protein 18 kDa (TSPO). Tanycyte-specific Tspo-knockout mice displayed reduced food consumption and weight loss associated with the downregulation of Agrp and Npy expression under high-fat diet feeding. Tspo-deficient tanycytes had elevated levels of intracellular ATP, which was released via connexin 43 hemichannels and extracellularly converted into adenosine by tanycytic ectonucleotidases. The adenosine signal was perceived by adenosine A1 receptors on adjacent AGRP/NPY neurons, reducing ERK phosphorylation, which in turn downregulated Agrp and Npy expression. Our findings underscore the anorexic role of adenosine as a gliotransmitter in the intricate communication between tanycytes and neurons for regulating appetite and body weight. (Figure presented.) © The Author(s) 2025. 2025-04-30T15:00:00Z