Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression

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dc.citation.epage35283en_US
dc.citation.issueNumber23en_US
dc.citation.spage35270en_US
dc.citation.volumeNumber7en_US
dc.contributor.authorChang, C.en_US
dc.contributor.authorZhang, C.en_US
dc.contributor.authorZhang, Q.en_US
dc.contributor.authorSahin, O.en_US
dc.contributor.authorWang, H.en_US
dc.contributor.authorXu, J.en_US
dc.contributor.authorXiao, Y.en_US
dc.contributor.authorZhang, J.en_US
dc.contributor.authorRehman, S. K.en_US
dc.contributor.authorLi, P.en_US
dc.contributor.authorHung, M. C.en_US
dc.contributor.authorBehbod, F.en_US
dc.contributor.authorYu, D.en_US
dc.date.accessioned2019-02-07T13:20:21Z
dc.date.available2019-02-07T13:20:21Z
dc.date.issued2016-05en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractMetabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby sustaining rapid proliferation. Recently, new evidence has emerged that metabolic dysregulation may occur at early-stages of neoplasia and critically contribute to cancer initiation. Here, our bioinformatics analysis of microarray data from early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of canonical glycolytic genes, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human mammary epithelial cells (hMECs) up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation. Knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Mechanistically, 14-3-3ζ overexpression activates the MEK-ERK-CREB axis, which subsequently up-regulates LDHA. In vivo, inhibiting the activated the MEK/ERK pathway in 14-3-3ζ-overexpressing hMEC-derived MCF10DCIS.COM lesions led to effective inhibition of tumor growth. Therefore, targeting the MEK/ERK pathway could be an effective strategy for intervention of 14-3-3ζ-overexpressing early breast lesions. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis and transcriptionally up-regulating LDHA, thereby contributes to human breast cancer initiation.en_US
dc.identifier.doi10.18632/oncotarget.9136en_US
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11693/49044
dc.language.isoEnglishen_US
dc.publisherImpact Journals LLCen_US
dc.relation.isversionofhttps://dx.doi.org/10.18632/oncotarget.9136en_US
dc.source.titleOncotargeten_US
dc.subjectLDHAen_US
dc.subject14-3-3ζen_US
dc.subjectGlycolysisen_US
dc.subjectCancer metabolismen_US
dc.subjectBreast cancer initiationen_US
dc.titleUpregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progressionen_US
dc.typeArticleen_US

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