Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

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• dc.contributor.author Váraljai, Renátaca
• dc.contributor.author Islam, Abul, 1978-ca
• dc.contributor.author Beshiri, Michael L.ca
• dc.contributor.author Rehman, Jaleesca
• dc.contributor.author López Bigas, Núriaca
• dc.contributor.author Benevolenskaya, Elizaveta V.ca
• dc.date.accessioned 2016-02-10T17:12:47Z
• dc.date.available 2016-03-01T03:00:03Z
• dc.date.issued 2015
• dc.description.abstract The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.ca
• dc.description.sponsorship This work was supported by R01CA138631 (to E.V.B.) and R01GM094220 (to J.R.) from the National Institutes of Health, educational grant SAF2009-06954 (to N.L.-B.) from the Spanish Ministry of Science, and a fellowship from the Agencia de Gestió d'Ajuts Universitaris i de Recerca of the Catalonian Government, Spain (to A.B.M.M.K.I.)
• dc.format.mimetype application/pdfca
• dc.identifier.citation Váraljai R, Islam AB, Beshiri ML, Rehman J, Lopez-Bigas N, Benevolenskaya EV. Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells. Genes & Development. 2015;29(17):1817-34. DOI: 10.1101/gad.264036.115ca
• dc.identifier.doi http://dx.doi.org/10.1101/gad.264036.115
• dc.identifier.issn 0890-9369
• dc.identifier.uri http://hdl.handle.net/10230/25775
• dc.language.iso engca
• dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)ca
• dc.relation.ispartof Genes & Development. 2015;29(17):1817-34
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-06954
• dc.rights © Published originally by Cold Spring Harbor Laboratory Press at http://dx.doi.org/10.1101/gad.264036.115. Beginning six months from the full-issue publication date, articles are distributed under the Creative Commons Attribution-Non-Commercial 4.0 International License (CC-BY-NC), as described at http://creativecommons.org/licenses/by-nc/4.0/. This license permits non-commercial use, including reproduction, adaptation, and distribution of the article provided the original author and source are credited.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/ca
• dc.subject.keyword KDM5A
• dc.subject.keyword RBP2
• dc.subject.keyword Differentiation
• dc.subject.keyword Histone methylation
• dc.subject.keyword Mitochondria
• dc.subject.keyword pRB
• dc.subject.other Histonesca
• dc.subject.other Mitocondrisca
• dc.title Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cellsca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca