作者: Appelberg, Sofia ; Mikaeloff, Flora ; Gupta, Soham ; Neogi, Ujjwal ; Mirazimi, Ali ; Ahlén, Gustaf ; Nikouyan, Negin ; Yan, Jingyi ; Revanna, Chandrashekar Bangalore ; Rezene, Sefanit ; Ambikan, Anoop ; Sällberg, Matti

Understanding how infection and vaccination reshape systemic metabolism is key to defining protective immunity against SARS-CoV-2. Using a ferret model, we performed untargeted serum metabolomics in two experimental settings: SARS-CoV-2 infection alone, and vaccination followed by viral challenge. Ferrets were immunized with four vaccines: a multigenic DNA-construct encoding receptor-binding domain, membrane, and nucleoprotein (OC2); a nucleoprotein-only DNA vaccine (OC12); a recombinant spike protein with QS-21 adjuvant (S+QS21); or a control hepatitis-B/D DNA vaccine (Hep-B/D). SARS-CoV-2 infection induced distinct systemic changes, including reduced lipid remodeling and enrichment of amino acid, carbohydrate, and energy pathways (notably glutathione and methionine-cysteine metabolism and the tricarboxylic acid cycle). Vaccination induced broader, immunogen-specific metabolic remodeling. Post-vaccination, S+QS21 triggered extensive early alterations, mainly suppressing lipid and amino acid pathways. In contrast, OC2 produced balanced remodeling across amino acid, lipid, nucleotide, and glutathione-related metabolism, with temporally consistent shifts. Following viral challenge, OC2 maintained sustained remodeling with enrichment of redox-associated metabolites, including γ-glutamyl amino acids and acylcarnitines, coinciding with anti-spike and anti-nucleoprotein IgG responses and complete viral clearance. OC12 elicited strong anti-nucleoprotein antibodies but limited remodeling and incomplete protection, while S+QS21 showed moderate post-challenge responses with partial clearance. Hep-B/D induced minimal changes and no protection. These findings show vaccination induces immunogen-specific metabolic programs, with OC2 eliciting the broadest remodeling linked to protective immunity. To our knowledge, this is the first demonstration that DNA-based multigenic SARS-CoV-2 vaccination induces systemic metabolic reprogramming in ferrets, linking remodeling to antibody responses and viral clearance. Metabolomics informs host-vaccine interactions within a systems vaccinology framework.

2024-12-01·CELLULAR AND MOLECULAR LIFE SCIENCES

Knockout of onecut2 inhibits proliferation and promotes apoptosis of tumor cells through SKP2-mediated p53 acetylation in hepatocellular carcinoma

Article

作者: Zhou, Jieling ; Guo, Xinhua ; Li, Cunjie ; Deng, Ning ; Xiao, Yuxin ; Zhao, Jianfu ; Zhang, Ligang ; Song, Xinran ; Liu, Shifeng ; Song, Qifang

Onecut2 (OC2) plays a vital regulatory role in tumor growth, metastasis and angiogenesis. In this study, we report the regulatory role and specific molecular mechanism of OC2 in the apoptosis of hepatocellular carcinoma (HCC) cells. We found that OC2 knockout via the CRISPR/CAS9 system not only significantly inhibited the proliferation and angiogenesis of HCC cells but also significantly promoted apoptosis. The apoptosis rate of the OC2 knockout HCC cell line reached 30.514%. In a mouse model, the proliferation inhibition rate of tumor cells reached 98.8%. To explore the mechanism of apoptosis, ChIP-Seq and dual-luciferase reporter assays were carried out. The results showed that OC2 could directly bind to the promotor of SKP2 and regulate its expression. Moreover, downregulating the expression of OC2 and SKP2 could release p300, promote the acetylation of p53, increase the expression of p21 and p27, and promote the apoptosis of HCC cells. Moreover, the overexpression of OC2 or SKP2 in the knockout HCC cell line clearly inhibited the acetylation level of p53 and reduced cell apoptosis. This study revealed that OC2 could regulate the apoptosis of HCC cells through the SKP2/p53/p21 axis, which may provide some therapeutic targets for HCC in the clinic.

2023-10-12·bioRxiv : the preprint server for biology

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer.

作者: Zhang, Baohui ; Cadaneanu, Radu M ; Freeman, Michael R ; Yang, Qian ; Yan, Yiwu ; Huang, Rongrong ; Ye, Huihui ; Garraway, Isla P ; Campbell, Moray J ; Kim, Hyoyoung ; Posadas, Edwin M ; Mostaghel, Elahe A ; Freedland, Stephen J ; Knudsen, Beatrice S ; Morrissey, Colm ; Brady, Lauren ; Nelson, Peter S ; Vizio, Dolores Di ; Ellis, Leigh ; Rotinen, Mirja ; Qian, Chen ; You, Sungyong ; Yang, Wei ; Kaochar, Salma ; Gallent, Brad ; Murali, Ramachandran

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

100 项与 OC-2 相关的药物交易

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