{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:41:42Z","timestamp":1793814102154,"version":"4.6.1"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA270234"],"award-info":[{"award-number":["R01CA270234"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["U54CA274329"],"award-info":[{"award-number":["U54CA274329"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA163649"],"award-info":[{"award-number":["R01CA163649"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA256911"],"award-info":[{"award-number":["R01CA256911"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R37CA276924"],"award-info":[{"award-number":["R37CA276924"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Cell Biol"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP\u2013seq and RNA\u2013seq analyses revealed alterations in polyamine homeostasis through regulation of\n                    <jats:italic>SAT1<\/jats:italic>\n                    gene expression and enrichment of the\n                    <jats:italic>SP1<\/jats:italic>\n                    -responsive signature. We identified acetate\/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2\u2013SP1\u2013SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2\u2013SP1\u2013SAT1 axis.\n                  <\/jats:p>","DOI":"10.1038\/s41556-024-01372-4","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T06:02:01Z","timestamp":1709272921000},"page":"613-627","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2\u2013SP1\u2013SAT1 axis"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6492-1894","authenticated-orcid":false,"given":"Divya","family":"Murthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-5245","authenticated-orcid":false,"given":"Kuldeep S.","family":"Attri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra K.","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2505-9757","authenticated-orcid":false,"given":"Ravi","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina V.","family":"Chaika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbo","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanupriya","family":"Jha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesha","family":"Dasgupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2081-3327","authenticated-orcid":false,"given":"Ryan J.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Mulder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Souchek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1489-4813","authenticated-orcid":false,"given":"Teklab","family":"Gebregiworgis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-2341","authenticated-orcid":false,"given":"Vikant","family":"Rai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8432-4616","authenticated-orcid":false,"given":"Rohit","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Sundeep","family":"Kollala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Pacheco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Grandgenett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-5788","authenticated-orcid":false,"given":"Fang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey J.","family":"Lazenby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1560-6921","authenticated-orcid":false,"given":"Adrian R.","family":"Black","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-2283","authenticated-orcid":false,"given":"Susanna","family":"Ulahannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barish H.","family":"Edil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9963-8909","authenticated-orcid":false,"given":"David L.","family":"Klinkebiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-6837","authenticated-orcid":false,"given":"Robert","family":"Powers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-0203","authenticated-orcid":false,"given":"Amarnath","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5255-8888","authenticated-orcid":false,"given":"Michael A.","family":"Hollingsworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamiya","family":"Mehla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Ly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4821-7017","authenticated-orcid":false,"given":"Sarika","family":"Chaudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa F.","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2281-0042","authenticated-orcid":false,"given":"Kathryn E.","family":"Wellen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8903-0131","authenticated-orcid":false,"given":"Pankaj K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,1]]},"reference":[{"key":"1372_CR1","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1053\/j.gastro.2004.12.036","volume":"128","author":"MG Bachem","year":"2005","unstructured":"Bachem, M. G. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907\u2013921 (2005).","journal-title":"Gastroenterology"},{"key":"1372_CR2","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.ccr.2014.04.021","volume":"25","author":"AD Rhim","year":"2014","unstructured":"Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735\u2013747 (2014).","journal-title":"Cancer Cell"},{"key":"1372_CR3","doi-asserted-by":"publisher","first-page":"E3091","DOI":"10.1073\/pnas.1411679111","volume":"111","author":"JJ Lee","year":"2014","unstructured":"Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091\u2013E3100 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1372_CR4","doi-asserted-by":"publisher","first-page":"5937","DOI":"10.1158\/1078-0432.CCR-14-1269","volume":"20","author":"EJ Kim","year":"2014","unstructured":"Kim, E. J. et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin. Cancer Res. 20, 5937\u20135945 (2014).","journal-title":"Clin. Cancer Res."},{"key":"1372_CR5","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1073\/pnas.1620164114","volume":"114","author":"MH Sherman","year":"2017","unstructured":"Sherman, M. H. et al. Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc. Natl Acad. Sci. USA 114, 1129\u20131134 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1372_CR6","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1038\/nature19084","volume":"536","author":"CM Sousa","year":"2016","unstructured":"Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479\u2013483 (2016).","journal-title":"Nature"},{"key":"1372_CR7","doi-asserted-by":"publisher","first-page":"5881","DOI":"10.1158\/1078-0432.CCR-17-1151","volume":"23","author":"V Gunda","year":"2017","unstructured":"Gunda, V. et al. MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer. Clin. Cancer Res. 23, 5881\u20135891 (2017).","journal-title":"Clin. Cancer Res."},{"key":"1372_CR8","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1053\/j.gastro.2021.06.045","volume":"161","author":"T Hu","year":"2021","unstructured":"Hu, T. et al. Metabolic rewiring by loss of Sirt5 promotes Kras-induced pancreatic cancer progression. Gastroenterology 161, 1584\u20131600 (2021).","journal-title":"Gastroenterology"},{"key":"1372_CR9","doi-asserted-by":"publisher","first-page":"104483","DOI":"10.1016\/j.isci.2022.104483","volume":"25","author":"MM Islam","year":"2022","unstructured":"Islam, M. M., Goertzen, A., Singh, P. K. & Saha, R. Exploring the metabolic landscape of pancreatic ductal adenocarcinoma cells using genome-scale metabolic modeling. iScience 25, 104483 (2022).","journal-title":"iScience"},{"key":"1372_CR10","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/s41388-021-02132-6","volume":"41","author":"RJ King","year":"2022","unstructured":"King, R. J. et al. CD73 induces GM-CSF\/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis. Oncogene 41, 971\u2013982 (2022).","journal-title":"Oncogene"},{"key":"1372_CR11","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1158\/1078-0432.CCR-19-2926","volume":"26","author":"K Mehla","year":"2020","unstructured":"Mehla, K. & Singh, P. K. Metabolic subtyping for novel personalized therapies against pancreatic cancer. Clin. Cancer Res. 26, 6\u20138 (2020).","journal-title":"Clin. Cancer Res."},{"key":"1372_CR12","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/s41568-023-00557-7","volume":"23","author":"NJ Mullen","year":"2023","unstructured":"Mullen, N. J. & Singh, P. K. Nucleotide metabolism: a pan-cancer metabolic dependency. Nat. Rev. Cancer 23, 275\u2013294 (2023).","journal-title":"Nat. Rev. Cancer"},{"key":"1372_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215981","volume":"552","author":"NJ Mullen","year":"2023","unstructured":"Mullen, N. J. et al. ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer. Cancer Lett. 552, 215981 (2023).","journal-title":"Cancer Lett."},{"key":"1372_CR14","doi-asserted-by":"publisher","first-page":"3381","DOI":"10.1038\/s41388-020-1225-4","volume":"39","author":"AA Olou","year":"2020","unstructured":"Olou, A. A., King, R. J., Yu, F. & Singh, P. K. MUC1 oncoprotein mitigates ER stress via CDA-mediated reprogramming of pyrimidine metabolism. Oncogene 39, 3381\u20133395 (2020).","journal-title":"Oncogene"},{"key":"1372_CR15","doi-asserted-by":"publisher","first-page":"5503","DOI":"10.1158\/0008-5472.CAN-16-3062","volume":"77","author":"S Tadros","year":"2017","unstructured":"Tadros, S. et al. De novo lipid synthesis facilitates gemcitabine resistance through endoplasmic reticulum stress in pancreatic cancer. Cancer Res. 77, 5503\u20135517 (2017).","journal-title":"Cancer Res."},{"key":"1372_CR16","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/cancers12010002","volume":"12","author":"E Vernucci","year":"2019","unstructured":"Vernucci, E. et al. Metabolic alterations in pancreatic cancer progression. Cancers (Basel) 12, 2 (2019).","journal-title":"Cancers (Basel)"},{"key":"1372_CR17","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ccell.2017.06.004","volume":"32","author":"SK Shukla","year":"2017","unstructured":"Shukla, S. K. et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell 32, 71\u201387 (2017).","journal-title":"Cancer Cell"},{"key":"1372_CR18","doi-asserted-by":"publisher","first-page":"e32996","DOI":"10.1371\/journal.pone.0032996","volume":"7","author":"NV Chaika","year":"2012","unstructured":"Chaika, N. V. et al. Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma. PLoS ONE 7, e32996 (2012).","journal-title":"PLoS ONE"},{"key":"1372_CR19","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.cmet.2015.05.014","volume":"21","author":"F Pietrocola","year":"2015","unstructured":"Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805\u2013821 (2015).","journal-title":"Cell Metab."},{"key":"1372_CR20","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.molcel.2017.06.008","volume":"67","author":"S Sivanand","year":"2017","unstructured":"Sivanand, S. et al. Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Mol. Cell 67, 252\u2013265 (2017).","journal-title":"Mol. Cell"},{"key":"1372_CR21","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.molcel.2018.07.015","volume":"71","author":"SL Campbell","year":"2018","unstructured":"Campbell, S. L. & Wellen, K. E. Metabolic signaling to the nucleus in cancer. Mol. Cell 71, 398\u2013408 (2018).","journal-title":"Mol. Cell"},{"key":"1372_CR22","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.2967\/jnumed.108.055087","volume":"49","author":"JW Park","year":"2008","unstructured":"Park, J. W. et al. A prospective evaluation of 18F-FDG and 11C-acetate PET\/CT for detection of primary and metastatic hepatocellular carcinoma. J. Nucl. Med. 49, 1912\u20131921 (2008).","journal-title":"J. Nucl. Med."},{"key":"1372_CR23","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.nucmedbio.2007.11.004","volume":"35","author":"T Tsuchida","year":"2008","unstructured":"Tsuchida, T., Takeuchi, H., Okazawa, H., Tsujikawa, T. & Fujibayashi, Y. Grading of brain glioma with 1-11C-acetate PET: comparison with 18F-FDG PET. Nucl. Med. Biol. 35, 171\u2013176 (2008).","journal-title":"Nucl. Med. Biol."},{"key":"1372_CR24","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.cmet.2014.06.004","volume":"20","author":"JV Lee","year":"2014","unstructured":"Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306\u2013319 (2014).","journal-title":"Cell Metab."},{"key":"1372_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11960","volume":"7","author":"X Gao","year":"2016","unstructured":"Gao, X. et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016).","journal-title":"Nat. Commun."},{"key":"1372_CR26","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.canlet.2017.04.029","volume":"400","author":"J Abrego","year":"2017","unstructured":"Abrego, J. et al. GOT1-mediated anaplerotic glutamine metabolism regulates chronic acidosis stress in pancreatic cancer cells. Cancer Lett. 400, 37\u201346 (2017).","journal-title":"Cancer Lett."},{"key":"1372_CR27","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1016\/j.celrep.2017.02.006","volume":"18","author":"A Kondo","year":"2017","unstructured":"Kondo, A. et al. Extracellular acidic pH activates the sterol regulatory element-binding protein 2 to promote tumor progression. Cell Rep. 18, 2228\u20132242 (2017).","journal-title":"Cell Rep."},{"key":"1372_CR28","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/nrc.2017.77","volume":"17","author":"C Corbet","year":"2017","unstructured":"Corbet, C. & Feron, O. Tumour acidosis: from the passenger to the driver\u2019s seat. Nat. Rev. Cancer 17, 577\u2013593 (2017).","journal-title":"Nat. Rev. Cancer"},{"key":"1372_CR29","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.ccr.2005.04.023","volume":"7","author":"SR Hingorani","year":"2005","unstructured":"Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469\u2013483 (2005).","journal-title":"Cancer Cell"},{"key":"1372_CR30","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.celrep.2016.09.069","volume":"17","author":"S Zhao","year":"2016","unstructured":"Zhao, S. et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 17, 1037\u20131052 (2016).","journal-title":"Cell Rep."},{"key":"1372_CR31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/fnene.2013.00011","volume":"5","author":"JR Moffett","year":"2013","unstructured":"Moffett, J. R., Arun, P., Ariyannur, P. S. & Namboodiri, A. M. N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis and protein acetylation. Front. Neuroenergetics 5, 11 (2013).","journal-title":"Front. Neuroenergetics"},{"key":"1372_CR32","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1158\/0008-5472.CAN-03-3645","volume":"64","author":"SJ Kridel","year":"2004","unstructured":"Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070\u20132075 (2004).","journal-title":"Cancer Res."},{"key":"1372_CR33","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1158\/2159-8290.CD-18-0567","volume":"9","author":"A Carrer","year":"2019","unstructured":"Carrer, A. et al. Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416\u2013435 (2019).","journal-title":"Cancer Discov."},{"key":"1372_CR34","doi-asserted-by":"publisher","first-page":"5834","DOI":"10.1073\/pnas.1303708110","volume":"110","author":"D Weerakkody","year":"2013","unstructured":"Weerakkody, D. et al. Family of pH (low) insertion peptides for tumor targeting. Proc. Natl Acad. Sci. USA 110, 5834\u20135839 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1372_CR35","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/0006-2952(92)90424-H","volume":"44","author":"PR Libby","year":"1992","unstructured":"Libby, P. R. & Porter, C. W. Inhibition of enzymes of polyamine back-conversion by pentamidine and berenil. Biochem. Pharmacol. 44, 830\u2013832 (1992).","journal-title":"Biochem. Pharmacol."},{"key":"1372_CR36","doi-asserted-by":"publisher","first-page":"3651","DOI":"10.1093\/nar\/gkg605","volume":"31","author":"D Farre","year":"2003","unstructured":"Farre, D. et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 31, 3651\u20133653 (2003).","journal-title":"Nucleic Acids Res."},{"key":"1372_CR37","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1093\/bioinformatics\/18.2.333","volume":"18","author":"X Messeguer","year":"2002","unstructured":"Messeguer, X. et al. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18, 333\u2013334 (2002).","journal-title":"Bioinformatics"},{"key":"1372_CR38","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1128\/MCB.26.5.1770-1785.2006","volume":"26","author":"JJ Hung","year":"2006","unstructured":"Hung, J. J., Wang, Y. T. & Chang, W. C. Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol. Cell. Biol. 26, 1770\u20131785 (2006).","journal-title":"Mol. Cell. Biol."},{"key":"1372_CR39","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1158\/0008-5472.CAN-09-3282","volume":"70","author":"Z Jia","year":"2010","unstructured":"Jia, Z. et al. Combined treatment of pancreatic cancer with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic antitumor activity. Cancer Res. 70, 1111\u20131119 (2010).","journal-title":"Cancer Res."},{"key":"1372_CR40","first-page":"149","volume":"10","author":"G Shin","year":"2011","unstructured":"Shin, G. et al. GENT: gene expression database of normal and tumor tissues. Cancer Inf. 10, 149\u2013157 (2011).","journal-title":"Cancer Inf."},{"key":"1372_CR41","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-019-0514-7","volume":"12","author":"SJ Park","year":"2019","unstructured":"Park, S. J., Yoon, B. H., Kim, S. K. & Kim, S. Y. GENT2: an updated gene expression database for normal and tumor tissues. BMC Med. Genomics 12, 101 (2019).","journal-title":"BMC Med. Genomics"},{"key":"1372_CR42","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1053\/j.gastro.2017.11.280","volume":"154","author":"C Vennin","year":"2018","unstructured":"Vennin, C. et al. Reshaping the tumor stroma for treatment of pancreatic cancer. Gastroenterology 154, 820\u2013838 (2018).","journal-title":"Gastroenterology"},{"key":"1372_CR43","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/s41580-019-0123-5","volume":"20","author":"J Zhu","year":"2019","unstructured":"Zhu, J. & Thompson, C. B. Metabolic regulation of cell growth and proliferation. Nat. Rev. Mol. Cell Biol. 20, 436\u2013450 (2019).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1372_CR44","doi-asserted-by":"publisher","first-page":"5221","DOI":"10.1073\/pnas.0409184102","volume":"102","author":"CN Madhavarao","year":"2005","unstructured":"Madhavarao, C. N. et al. Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan\u2019s disease. Proc. Natl Acad. Sci. USA 102, 5221\u20135226 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1372_CR45","doi-asserted-by":"publisher","first-page":"13557","DOI":"10.1093\/nar\/gku885","volume":"42","author":"A Suzuki","year":"2014","unstructured":"Suzuki, A. et al. Aberrant transcriptional regulations in cancers: genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines. Nucleic Acids Res. 42, 13557\u201313572 (2014).","journal-title":"Nucleic Acids Res."},{"key":"1372_CR46","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.celrep.2016.12.055","volume":"18","author":"V Bulusu","year":"2017","unstructured":"Bulusu, V. et al. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Rep. 18, 647\u2013658 (2017).","journal-title":"Cell Rep."},{"key":"1372_CR47","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nrd2243","volume":"6","author":"RA Casero Jr.","year":"2007","unstructured":"Casero, R. A. Jr. & Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat. Rev. Drug Discov. 6, 373\u2013390 (2007).","journal-title":"Nat. Rev. Drug Discov."},{"key":"1372_CR48","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1093\/nar\/22.14.2784","volume":"22","author":"M Frugier","year":"1994","unstructured":"Frugier, M., Florentz, C., Hosseini, M. W., Lehn, J. M. & Giege, R. Synthetic polyamines stimulate in vitro transcription by T7 RNA polymerase. Nucleic Acids Res. 22, 2784\u20132790 (1994).","journal-title":"Nucleic Acids Res."},{"key":"1372_CR49","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.biocel.2013.02.021","volume":"45","author":"T Yamashita","year":"2013","unstructured":"Yamashita, T. et al. Role of polyamines at the G1\/S boundary and G2\/M phase of the cell cycle. Int. J. Biochem. Cell Biol. 45, 1042\u20131050 (2013).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"1372_CR50","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/(SICI)1097-4644(20000601)77:3<345::AID-JCB1>3.0.CO;2-P","volume":"77","author":"CA Hobbs","year":"2000","unstructured":"Hobbs, C. A. & Gilmour, S. K. High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation. J. Cell. Biochem. 77, 345\u2013360 (2000).","journal-title":"J. Cell. Biochem."},{"key":"1372_CR51","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/s41568-018-0050-3","volume":"18","author":"RA Casero Jr","year":"2018","unstructured":"Casero, R. A. Jr, Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681\u2013695 (2018).","journal-title":"Nat. Rev. Cancer"},{"key":"1372_CR52","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.gene.2005.09.010","volume":"363","author":"MA Glozak","year":"2005","unstructured":"Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 363, 15\u201323 (2005).","journal-title":"Gene"},{"key":"1372_CR53","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","volume":"68","author":"RF Hwang","year":"2008","unstructured":"Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918\u2013926 (2008).","journal-title":"Cancer Res."},{"key":"1372_CR54","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.cell.2014.12.021","volume":"160","author":"SF Boj","year":"2015","unstructured":"Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324\u2013338 (2015).","journal-title":"Cell"},{"key":"1372_CR55","doi-asserted-by":"publisher","first-page":"13787","DOI":"10.1073\/pnas.1203339109","volume":"109","author":"NV Chaika","year":"2012","unstructured":"Chaika, N. V. et al. MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc. Natl Acad. Sci. USA 109, 13787\u201313792 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1372_CR56","doi-asserted-by":"publisher","first-page":"e0154416","DOI":"10.1371\/journal.pone.0154416","volume":"11","author":"V Gunda","year":"2016","unstructured":"Gunda, V., Yu, F. & Singh, P. K. Validation of metabolic alterations in microscale cell culture lysates using hydrophilic interaction liquid chromatography (HILIC)-tandem mass spectrometry-based metabolomics. PLoS One 11, e0154416 (2016).","journal-title":"PLoS One"},{"key":"1372_CR57","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20820-4","volume":"8","author":"KS Attri","year":"2018","unstructured":"Attri, K. S., Mehla, K., Shukla, S. K. & Singh, P. K. Microscale gene expression analysis of tumor-associated macrophages. Sci. Rep. 8, 2408 (2018).","journal-title":"Sci. Rep."},{"key":"1372_CR58","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1016\/j.cell.2014.11.020","volume":"159","author":"SA Comerford","year":"2014","unstructured":"Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591\u20131602 (2014).","journal-title":"Cell"},{"key":"1372_CR59","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.1923","volume":"9","author":"B Langmead","year":"2012","unstructured":"Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357\u2013359 (2012).","journal-title":"Nat. Methods"},{"key":"1372_CR60","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137","volume":"9","author":"Y Zhang","year":"2008","unstructured":"Zhang, Y. et al. Model-based analysis of ChIP-seq (MACS). Genome Biol. 9, R137 (2008).","journal-title":"Genome Biol."},{"key":"1372_CR61","doi-asserted-by":"publisher","first-page":"e128","DOI":"10.1093\/nar\/gks433","volume":"40","author":"TL Bailey","year":"2012","unstructured":"Bailey, T. L. & Machanick, P. Inferring direct DNA binding from ChIP-seq. Nucleic Acids Res. 40, e128 (2012).","journal-title":"Nucleic Acids Res."},{"key":"1372_CR62","doi-asserted-by":"crossref","first-page":"D87","DOI":"10.1093\/nar\/gkaa516","volume":"48","author":"O Fornes","year":"2020","unstructured":"Fornes, O. et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 48, D87\u2013D92 (2020).","journal-title":"Nucleic Acids Res."},{"key":"1372_CR63","first-page":"2016","volume":"55","author":"L Badea","year":"2008","unstructured":"Badea, L., Herlea, V., Dima, S. O., Dumitrascu, T. & Popescu, I. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology 55, 2016\u20132027 (2008).","journal-title":"Hepatogastroenterology"},{"key":"1372_CR64","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nmeth.3213","volume":"12","author":"J Yang","year":"2015","unstructured":"Yang, J. et al. The I-TASSER Suite: protein structure and function prediction. Nat. Methods 12, 7\u20138 (2015).","journal-title":"Nat. Methods"},{"key":"1372_CR65","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1016\/j.bbrc.2006.08.199","volume":"350","author":"A Li","year":"2006","unstructured":"Li, A., Xue, Y., Jin, C., Wang, M. & Yao, X. Prediction of N\u03b5-acetylation on internal lysines implemented in Bayesian Discriminant Method. Biochem. Biophys. Res. Commun. 350, 818\u2013824 (2006).","journal-title":"Biochem. Biophys. Res. Commun."}],"updated-by":[{"DOI":"10.1038\/s41556-024-01417-8","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000}},{"DOI":"10.1038\/s41556-026-02055-y","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000}}],"container-title":["Nature Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41556-024-01372-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41556-024-01372-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41556-024-01372-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T07:02:05Z","timestamp":1785913325000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41556-024-01372-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,1]]},"references-count":65,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["1372"],"URL":"https:\/\/doi.org\/10.1038\/s41556-024-01372-4","relation":{},"ISSN":["1465-7392","1476-4679"],"issn-type":[{"value":"1465-7392","type":"print"},{"value":"1476-4679","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,1]]},"assertion":[{"value":"21 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2024","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41556-024-01417-8","URL":"https:\/\/doi.org\/10.1038\/s41556-024-01417-8","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2026","order":9,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":10,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41556-026-02055-y","URL":"https:\/\/doi.org\/10.1038\/s41556-026-02055-y","order":12,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}