bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–10–13
six papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Histone lactylation drives CD8+ T cell metabolism and function.
  2. Metabolite regulation of epigenetics in cancer.
  3. O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation.
  4. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
  5. FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1.
  6. Ethionine-induced S-adenosylmethionine deficiency suppressed H3K27me3 and cell differentiation during neural tube development in mice.
  1. Nat Immunol. 2024 Oct 07.
    Histone lactylation drives CD8+ T cell metabolism and function.
    Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Mercedes Hennessey, Aminah J Tannir, Shrinidhi Byregowda, Seanu Meena Natarajan, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.
      The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01985-9
  2. Cell Rep. 2024 Oct 04. pii: S2211-1247(24)01166-5. [Epub ahead of print]43(10): 114815
    Metabolite regulation of epigenetics in cancer.
    Pu Wang, Lei-Lei Chen, Yue Xiong, Dan Ye.
      The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114815
  3. Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2402674121
    O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation.
    Jia Liu, Yang Wang, Miaomiao Tian, Mingjie Xia, Yi Zheng, Miao Hao, Yuqiang Qian, Hengyao Shu, Wenxia Zhang, Pinghui Peng, Zhexuan Zhao, Kejian Dong, Wanting Peng, Tian Gao, Zhanjun Li, Xin Jin, Min Wei, Yunpeng Feng.
      Elevated lipid synthesis is one of the best-characterized metabolic alterations in cancer and crucial for membrane expansion. As a key rate-limiting enzyme in de novo fatty acid synthesis, ATP-citrate lyase (ACLY) is frequently up-regulated in tumors and regulated by posttranslational modifications (PTMs). Despite emerging evidence showing O-GlcNAcylation on ACLY, its biological function still remains unknown. Here, we observed a significant upregulation of ACLY O-GlcNAcylation in various types of human tumor cells and tissues and identified S979 as a major O-GlcNAcylation site. Importantly, S979 O-GlcNAcylation is required for substrate CoA binding and crucial for ACLY enzymatic activity. Moreover, it is sensitive to glucose fluctuation and decisive for fatty acid synthesis as well as tumor cell proliferation. In response to EGF stimulation, both S979 O-GlcNAcylation and previously characterized S455 phosphorylation played indispensable role in the regulation of ACLY activity and cell proliferation; however, they functioned independently from each other. In vivo, streptozocin treatment- and EGFR overexpression-induced growth of xenograft tumors was mitigated once S979 was mutated. Collectively, this work helps comprehend how cells interrogate the nutrient enrichment for proliferation and suggests that although mammalian cell proliferation is controlled by mitogen signaling, the ancient nutrition-sensing mechanism is conserved and still efficacious in the cells of multicellular organisms.
    Keywords:  ATP-citrate lyase; CoA association; O-GlcNAcylation; fatty acid synthesis; tumor cell proliferation
    DOI:  https://doi.org/10.1073/pnas.2402674121
  4. Nat Commun. 2024 Oct 06. 15(1): 8658
    GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
    Justin A Guerrero, Dorota D Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J Svensson, Kara L Davis, Maya Kasowski, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
    DOI:  https://doi.org/10.1038/s41467-024-52666-y
  5. Commun Biol. 2024 Oct 10. 7(1): 1297
    FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1.
    Chenfei Dong, Yue Zhang, Jiayue Zeng, Suli Chong, Yang Liu, Ziming Bian, Sairong Fan, Xiaoming Chen.
      Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide because of its high rate of metastasis, and approximately 20% of CRC patients have metastases at initial diagnosis. Metabolic reprogramming, a hallmark of cancer cells, has been implicated in the process of metastasis. We previously demonstrated that fucosyltransferase 2 (FUT2) promotes the malignancy of CRC cells, however, the underlying mechanisms remain unclear. Here, bioinformatic analysis revealed that FUT2 is associated with the malignant phenotype and fatty acid metabolism in CRC. FUT2 knockdown decreased glucose uptake and de novo fatty acid synthesis, which in turn inhibited the proliferation and metastasis of CRC cells. Mechanistically, FUT2 promotes YAP1 nuclear translocation and stabilizes mSREBP-1 by fucosylation, thus promoting de novo fatty acid synthesis in CRC cells. In summary, this study demonstrates that FUT2 promotes the proliferation and metastasis of CRC cells by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1, indicating that FUT2 might be a potential target for developing therapeutic strategies against CRC.
    DOI:  https://doi.org/10.1038/s42003-024-06993-x
  6. J Cell Physiol. 2024 Oct 06. e31452
    Ethionine-induced S-adenosylmethionine deficiency suppressed H3K27me3 and cell differentiation during neural tube development in mice.
    Li Zhang, Xiaona Zhang, Yurong Liu, Kaixin Wei, Huijing Ma, Li Xia, Rui Cao, Yuqing Sun, Ronghua Zheng, Xiuwei Wang, Bingmei Chang.
      S-adenosylmethionine (SAM) as a major methyl donor plays a key role in methylation modification in vivo, and its disorder was closely related to neural tube defects (NTDs). However, the exact mechanism between SAM deficiency and NTDs remained unclearly. Hence, we investigated the association between histone methylation modification and cell differentiation in NTDs mice induced by SAM deficiency. The levels of SAM and SAH (S-adenosylhomocysteine) were determined by enzyme linked immunosorbent assay (ELISA). The level of histone methylation, β-catenin were analyzed by Western blot, reversing transcription and quantitative PCR (RT-qPCR) and immunofluorescence. The results showed that the incidence rate of NTDs induced by ethionine were 46.2%. Post treatment of ethionine combined with SAM, the incidence rate of NTDs was reduced to 26.2%. The level of SAM was significantly decreased (p < 0.05) and a reduction in the SAM/SAH ratio was observed after entionine treatment. The SAM deficiency caused the reduction of H3K27me3 modifications and the elevated UTX activity (p < 0.05), and inhibited the expressions of β-catenin. The differentiations of NSCs into neurons and oligodendrocytes were inhibited under SAM deficiency (p < 0.05). These results indicated that the SAM deficiency led to reduce H3K27me3 modifications, prevented the β-catenin signaling pathway and NSCs differentiation, which provided an understanding of the novel function of epigenetic regulation in NTDs.
    Keywords:  H3K27me3; S‐adenosylmethionine; differentiation; neural stem cells; neural tube defects
    DOI:  https://doi.org/10.1002/jcp.31452
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