A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells

dc.contributor.authorEduardo, Mariana Bustamante
dc.contributor.authorCottone, Gannon
dc.contributor.authorMcCloskey, Curtis W.
dc.contributor.authorLiu, Shiyu
dc.contributor.authorPalma, Flavio R.
dc.contributor.authorZappia, Maria Paula
dc.contributor.authorIslam, Abul B. M. M. K.
dc.contributor.authorGao, Peng
dc.contributor.authorSetya, Joel
dc.contributor.authorDennis, Saya
dc.contributor.authorGao, Hongyu
dc.contributor.authorZhang, Qian
dc.contributor.authorXuei, Xiaoling
dc.contributor.authorLuo, Yuan
dc.contributor.authorLocasale, Jason
dc.contributor.authorBonini, Marcelo G.
dc.contributor.authorKhokha, Rama
dc.contributor.authorFrolov, Maxim V.
dc.contributor.authorBenevolenskaya, Elizaveta V.
dc.contributor.authorChandel, Navdeep S.
dc.contributor.authorKhan, Seema A.
dc.contributor.authorClare, Susan E.
dc.contributor.departmentMedical and Molecular Genetics, School of Medicine
dc.date.accessioned2025-04-21T09:14:49Z
dc.date.available2025-04-21T09:14:49Z
dc.date.issued2025
dc.description.abstractLipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.
dc.eprint.versionFinal published version
dc.identifier.citationEduardo MB, Cottone G, McCloskey CW, et al. A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells. Sci Adv. 2025;11(12):eads9182. doi:10.1126/sciadv.ads9182
dc.identifier.urihttps://hdl.handle.net/1805/47202
dc.language.isoen_US
dc.publisherAmerican Association for the Advancement of Science
dc.relation.isversionof10.1126/sciadv.ads9182
dc.relation.journalScience Advances
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectBreast neoplasms
dc.subjectPhosphoglycerate dehydrogenase
dc.subjectGlutathione
dc.subjectSerine
dc.subjectReactive oxygen species
dc.titleA metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells
dc.typeArticle
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