{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T20:57:09Z","timestamp":1769979429775,"version":"3.49.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T00:00:00Z","timestamp":1587600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms\u2019 regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate\u2019s impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.<\/jats:p>","DOI":"10.3390\/cells9041053","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"1053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation"],"prefix":"10.3390","volume":"9","author":[{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0441-6356","authenticated-orcid":false,"given":"Ana","family":"Lameirinhas","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Master in Oncology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7434-8398","authenticated-orcid":false,"given":"Catarina","family":"Macedo-Silva","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Master in Oncology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar\u2013University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"Paula","family":"C. Dias","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"}]},{"given":"Ver\u00f3nica","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar\u2013University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology &amp; Epigenetics Group\u2014Research Center, Portuguese Oncology Institute of Porto (CI-IPOP), 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar\u2013University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"804","DOI":"10.6004\/jnccn.2017.0100","article-title":"Kidney cancer, version 2.2017, nccn clinical practice guidelines in oncology","volume":"15","author":"Motzer","year":"2017","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/jim-2018-000918","article-title":"Update on the biology and management of renal cell carcinoma","volume":"67","author":"Dutcher","year":"2019","journal-title":"J. Investig. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.radonc.2009.06.025","article-title":"Pyruvate into lactate and back: From the warburg effect to symbiotic energy fuel exchange in cancer cells","volume":"92","author":"Feron","year":"2009","journal-title":"Radiother. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.canlet.2020.02.034","article-title":"The metabolic landscape of urological cancers: New therapeutic perspectives","volume":"477","author":"Lameirinhas","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6921","DOI":"10.1158\/0008-5472.CAN-11-1457","article-title":"Lactate: A metabolic key player in cancer","volume":"71","author":"Hirschhaeuser","year":"2011","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.tibs.2018.10.011","article-title":"Lactate: A metabolic driver in the tumour landscape","volume":"44","author":"Ippolito","year":"2019","journal-title":"Trends Biochem. Sci."},{"key":"ref_10","first-page":"3835","article-title":"Tumor metabolism: Cancer cells give and take lactate","volume":"118","author":"Semenza","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.3389\/fonc.2019.01143","article-title":"Lactate in the regulation of tumor microenvironment and therapeutic approaches","volume":"9","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"a019497","DOI":"10.1101\/cshperspect.a019497","article-title":"Epigenetics and human disease","volume":"8","author":"Zoghbi","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13223-018-0259-4","article-title":"Histone modifications and their role in epigenetics of atopy and allergic diseases","volume":"14","author":"Khalaila","year":"2018","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eaal2380","DOI":"10.1126\/science.aal2380","article-title":"Epigenetic plasticity and the hallmarks of cancer","volume":"357","author":"Flavahan","year":"2017","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1038\/ncb3629","article-title":"The impact of cellular metabolism on chromatin dynamics and epigenetics","volume":"19","author":"Reid","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3389\/fgene.2018.00427","article-title":"Metabolism and epigenetic interplay in cancer: Regulation and putative therapeutic targets","volume":"9","author":"Lameirinhas","year":"2018","journal-title":"Front. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4794","DOI":"10.1093\/nar\/gks066","article-title":"Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression","volume":"40","author":"Latham","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12964-015-0114-x","article-title":"L- and d-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation","volume":"13","author":"Wagner","year":"2015","journal-title":"Cell Commun. Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1080\/14756366.2017.1417274","article-title":"Zinc binding groups for histone deacetylase inhibitors","volume":"33","author":"Zhang","year":"2018","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev.biochem.73.011303.073651","article-title":"The sir2 family of protein deacetylases","volume":"73","author":"Blander","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nrd3674","article-title":"Epigenetic protein families: A new frontier for drug discovery","volume":"11","author":"Arrowsmith","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-3-642-21631-2_2","article-title":"The biology of hdac in cancer: The nuclear and epigenetic components","volume":"206","author":"Hagelkruys","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/nrc3985","article-title":"The multifaceted functions of sirtuins in cancer","volume":"15","author":"Chalkiadaki","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fphar.2019.00038","article-title":"Dual tumor suppressor and tumor promoter action of sirtuins in determining malignant phenotype","volume":"10","author":"Carafa","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhao, E., Hou, J., Ke, X., Abbas, M.N., Kausar, S., Zhang, L., and Cui, H. (2019). The roles of sirtuin family proteins in cancer progression. Cancers, 11.","DOI":"10.3390\/cancers11121949"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1749-6632.2012.06762.x","article-title":"Janus-faced role of sirt1 in tumorigenesis","volume":"1271","author":"Song","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3031459","DOI":"10.1155\/2016\/3031459","article-title":"Sirtuins and cancer: Role in the epithelial-mesenchymal transition","volume":"2016","author":"Palmirotta","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46335","DOI":"10.18632\/oncotarget.10114","article-title":"Hypoxia-mediated upregulation of mct1 expression supports the glycolytic phenotype of glioblastomas","volume":"7","author":"Granja","year":"2016","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13148-015-0076-2","article-title":"Microrna-375 plays a dual role in prostate carcinogenesis","volume":"7","author":"Vieira","year":"2015","journal-title":"Clin. Epigenetics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1080\/14737140.2016.1222908","article-title":"Renal cell cancer: Overview of the current therapeutic landscape","volume":"16","author":"Erman","year":"2016","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-3-030-34025-4_3","article-title":"Lactate and lactate transporters as key players in the maintenance of the warburg effect","volume":"1219","author":"Afonso","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/nrc.2016.82","article-title":"Metabolic control of epigenetics in cancer","volume":"16","author":"Kinnaird","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lameirinhas, A., Miranda-Goncalves, V., Henrique, R., and Jeronimo, C. (2019). The complex interplay between metabolic reprogramming and epigenetic alterations in renal cell carcinoma. Genes, 10.","DOI":"10.3390\/genes10040264"},{"key":"ref_34","first-page":"22","article-title":"Sirtuins, metabolism, and cancer","volume":"3","author":"Mostoslavsky","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1158\/0008-5472.CAN-08-3365","article-title":"The critical role of the class iii histone deacetylase sirt1 in cancer","volume":"69","author":"Liu","year":"2009","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12943-016-0502-x","article-title":"Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications","volume":"15","author":"Maziveyi","year":"2016","journal-title":"Mol. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41419-019-1397-4","article-title":"Emt is associated with an epigenetic signature of ecm remodeling genes","volume":"10","author":"Peixoto","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109523","DOI":"10.1016\/j.cellsig.2019.109523","article-title":"Role of airway epithelial cells in the development of different asthma phenotypes","volume":"69","author":"Potaczek","year":"2020","journal-title":"Cell Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.celrep.2013.03.019","article-title":"Sirt1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis","volume":"3","author":"Simic","year":"2013","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1186\/1476-4598-13-254","article-title":"Role of sirt1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis","volume":"13","author":"Chen","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1093\/jnci\/djt118","article-title":"A sumoylation-dependent pathway regulates sirt1 transcription and lung cancer metastasis","volume":"105","author":"Sun","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_42","first-page":"3939","article-title":"Piasy mediates hypoxia-induced sirt1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells","volume":"126","author":"Sun","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1177\/1535370215598401","article-title":"Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-beta pathway on matrix metalloproteinase 7","volume":"241","author":"Xiao","year":"2016","journal-title":"Exp. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9007","DOI":"10.1002\/jcp.26846","article-title":"Sirt1 inhibits tgf-beta-induced endothelial-mesenchymal transition in human endothelial cells with smad4 deacetylation","volume":"233","author":"Li","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.molcel.2005.02.022","article-title":"Mechanism of sirtuin inhibition by nicotinamide: Altering the nad(+) cosubstrate specificity of a sir2 enzyme","volume":"17","author":"Avalos","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4473","DOI":"10.1158\/0008-5472.CAN-10-4452","article-title":"Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53\/mir-34a\/sirt1 tumor suppressor network","volume":"71","author":"Audrito","year":"2011","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1074\/jbc.M807869200","article-title":"Role of sirtuin histone deacetylase sirt1 in prostate cancer. A target for prostate cancer management via its inhibition?","volume":"284","author":"Nihal","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1093\/neuonc\/nos298","article-title":"Monocarboxylate transporters (mcts) in gliomas: Expression and exploitation as therapeutic targets","volume":"15","author":"Honavar","year":"2013","journal-title":"Neuro Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1227\/01.NEU.0000249218.65332.BF","article-title":"Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: An in vitro study","volume":"59","author":"Colen","year":"2006","journal-title":"Neurosurgery"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e248","DOI":"10.1038\/cddis.2011.123","article-title":"Cancer metabolism: Current perspectives and future directions","volume":"3","author":"Ricci","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_51","first-page":"1511","article-title":"Monocarboxylate transporters as targets and mediators in cancer therapy response","volume":"29","author":"Baltazar","year":"2014","journal-title":"Histol. Histopathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.yexcr.2011.11.014","article-title":"Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment","volume":"318","author":"Rattigan","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1002\/mc.22707","article-title":"Monocarboxylate transporter 1 is a key player in glioma-endothelial cell crosstalk","volume":"56","author":"Bezerra","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"675.e9","DOI":"10.1016\/j.urolonc.2017.08.016","article-title":"Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance","volume":"35","author":"Jeh","year":"2017","journal-title":"Urol. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1080\/10408398.2016.1263597","article-title":"Resveratrol as an anti-cancer agent: A review","volume":"58","author":"Rauf","year":"2018","journal-title":"Crit. Rev. Food Sci. Nutr."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/1053\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:09:05Z","timestamp":1760364545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/1053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,23]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["cells9041053"],"URL":"https:\/\/doi.org\/10.3390\/cells9041053","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,23]]}}}