MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation

Giorgio, Eros Di; Clocchiatti, Andrea; Piccinin, Sara; Sgorbissa, Andrea; Viviani, Giulia; Peruzzo, Paolo; Romeo, Salvatore; Rossi, Sabrina; Tos, Angelo Paolo Dei; Maestro, Roberta; Brancolini, Claudio

doi:10.1128/mcb.01050-13

Cited by 47 publications

(76 citation statements)

References 48 publications

(62 reference statements)

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“…1D). Although HDAC4/ TM-expressing cells display a proliferative advantage with respect to HDAC4/WT or GFP-expressing cells, 19 extracellular acidification was equivalent to the control cell lines, with the pH of the medium remaining around 7.8. In contrast, in RASexpressing cells extracellular acidification with a pH of 6.7 was evident.…”

Section: Resultsmentioning

confidence: 87%

“…1B) and tumor formation in immunocompromised mice. 19 The oncogenic properties of HDAC4/TM cells are comparable to cells expressing the RAS oncogene. By contrast, the expression of HDAC4/WT failed to induce overt growth in soft-agar and the number of colonies was comparable to GFP expressing cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…19,24 The list of genes down-and upregulated in NIH 3T3 cells expressing HDAC4/TM is shown in the supplementary table S1. Initially, we interrogated 5 curated MSigDB (H) genesets, representing a collection of genes encoding for proteins involved in common metabolic processes with the HDAC4/TM and RAS signatures.…”

Section: Different Regulation Of Metabolic Genes In Ras and Hdac4/tm-mentioning

confidence: 99%

“…Growth in soft agar and tumor formation in immunocompromised mice can be elicited by HDAC4 mutated in the 14-3-3 binding sites, similarly to RAS oncogene. 19 Oncogenic transformation is coupled to metabolic adaptations aimed to sustain the uncontrolled proliferative state. 20 The RAS proteins are key switchers, acting as nodes of the growth factors signaling pathway and exhibit a potent transforming potential.…”

Section: Introductionmentioning

confidence: 99%

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Transformation by different oncogenes relies on specific metabolic adaptations

et al. 2016

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Metabolic adaptations are emerging as common traits of cancer cells and tumor progression. In vitro transformation of NIH 3T3 cells allows the analysis of the metabolic changes triggered by a single oncogene. In this work, we have compared the metabolic changes induced by H-RAS and by the nuclear resident mutant of histone deacetylase 4 (HDAC4). RAS-transformed cells exhibit a dominant aerobic glycolytic phenotype characterized by up-regulation of glycolytic enzymes, reduced oxygen consumption and a defect in complex I activity. In this model of transformation, glycolysis is strictly required for sustaining the ATP levels and the robust cellular proliferation. By contrast, in HDAC4/TM transformed cells, glycolysis is only modestly up-regulated, lactate secretion is not augmented and, instead, mitochondrial oxygen consumption is increased. Our results demonstrate that cellular transformation can be accomplished through different metabolic adaptations and HDAC4/TM cells can represent a useful model to investigate oncogene-driven metabolic changes besides the Warburg effect.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Different Regulation Of Metabolic Genes In Ras and Hdac4/tm-mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transformation by different oncogenes relies on specific metabolic adaptations

et al. 2016

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“…The ligand-binding domain of the estrogen receptor was PCR amplified from pcDNA MEF2-VP16-ER (Flavell et al, 2006) and cloned into pWZLHygro. To generate pWZL-Hygro-HDAC7/SA-ER, an EcoRI-digested fragment of the HDAC7/SA point mutant (Di Giorgio et al, 2013) was cloned into pWZLHygro-ER. MCF10A cells expressing the MEF2-VP16-ER or HDAC7/SA-ER transgenes were generated by using retroviral infection, as described previously (Cernotta et al, 2011).…”

Section: Morphogenetic Assaymentioning

confidence: 99%

The MEF2-HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Clocchiatti

Giorgio

Viviani

et al. 2015

Journal of Cell Science

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The myocyte enhancer factor 2 and histone deacetylase (MEF2-HDAC) axis is a master regulator of different developmental programs and adaptive responses in adults. In this paper, we have investigated the contribution of the axis to the regulation of epithelial morphogenesis, using 3D organotypic cultures of MCF10A cells as a model. We have demonstrated that MEF2 transcriptional activity is upregulated during acini formation, which coincides with exit from the proliferative phase. Upregulation of the transcription of MEF2 proteins is coupled to downregulation of HDAC7, which occurs independently from changes in mRNA levels, and proteasome-or autophagymediated degradation. During acini formation, the MEF2-HDAC axis contributes to the promotion of cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells can HDAC7 bind to the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters and enhancers. In cells transformed by the oncogene HER2 (ERBB2), acini morphogenesis is altered, MEF2 transcription is repressed and HDAC7 is continuously expressed. Importantly, reactivation of MEF2 transcriptional activity in these cells, through the use of a HER2 inhibitor or by enhancing MEF2 function, corrected the proliferative defect and re-established normal acini morphogenesis.

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Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

2018

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Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well‐known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4‐TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene‐induced senescence). Unlike RAS, HDAC4‐induced OIS was TP53‐dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX‐positive foci. The inactivation of both TP53 and of the retinoblastoma (pRb) tumor suppressors, as induced by the viral oncogenes large and small T of SV40, triggers anchorage‐independent growth in RAS, HDAC4‐TM and, to a lesser extent, in HDAC4‐wild type (WT)‐expressing cells. Our results suggest an oncogenic function of class IIa HDACs in human cells, and justify further efforts to discover and evaluate isoform‐specific inhibitors of these epigenetic regulators from a therapeutic perspective.

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MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation

Cited by 47 publications

References 48 publications

Transformation by different oncogenes relies on specific metabolic adaptations

Transformation by different oncogenes relies on specific metabolic adaptations

The MEF2-HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

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