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

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...

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Autores principales: Váraljai, Renáta, Islam, Abul B.M.M.K., Beshiri, Michael L., Rehman, Jalees, Lopez-Bigas, Nuria, Benevolenskaya, Elizaveta V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573855/
https://www.ncbi.nlm.nih.gov/pubmed/26314709
http://dx.doi.org/10.1101/gad.264036.115
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author Váraljai, Renáta
Islam, Abul B.M.M.K.
Beshiri, Michael L.
Rehman, Jalees
Lopez-Bigas, Nuria
Benevolenskaya, Elizaveta V.
author_facet Váraljai, Renáta
Islam, Abul B.M.M.K.
Beshiri, Michael L.
Rehman, Jalees
Lopez-Bigas, Nuria
Benevolenskaya, Elizaveta V.
author_sort Váraljai, Renáta
collection PubMed
description 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.
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spelling pubmed-45738552016-03-01 Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells Váraljai, Renáta Islam, Abul B.M.M.K. Beshiri, Michael L. Rehman, Jalees Lopez-Bigas, Nuria Benevolenskaya, Elizaveta V. Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2015-09-01 /pmc/articles/PMC4573855/ /pubmed/26314709 http://dx.doi.org/10.1101/gad.264036.115 Text en © 2015 Váraljai et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Váraljai, Renáta
Islam, Abul B.M.M.K.
Beshiri, Michael L.
Rehman, Jalees
Lopez-Bigas, Nuria
Benevolenskaya, Elizaveta V.
Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title_full Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title_fullStr Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title_full_unstemmed Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title_short Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells
title_sort increased mitochondrial function downstream from kdm5a histone demethylase rescues differentiation in prb-deficient cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573855/
https://www.ncbi.nlm.nih.gov/pubmed/26314709
http://dx.doi.org/10.1101/gad.264036.115
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