Protein acetylation mechanisms in the regulation of insulin and insulin-like growth factor 1 signalling

Pirola, Luciano; Zerzaihi, Ouafa; Vidal, Hubert; Solari, Florence

doi:10.1016/j.mce.2012.05.011

Cited by 22 publications

(15 citation statements)

References 86 publications

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“…We, therefore, assume that a bidirectional interaction exists between the mTOR system and the epigenetic machinery in cancer cells, whereby the divergent Raptor behaviour points to differences in how both systems communicate. Adjustment of intracellular metabolic pathways is thought to be regulated by interplay between IGFr, Akt‐mTOR and de/acetylation events, which supports this assumption . Further experiments are intended to obtain more detailed insight into the fine tuning of the IGFr‐triggered TOR histone compared to the HDAC‐triggered histone‐mTOR connection.…”

Section: Discussionmentioning

confidence: 71%

Cross‐communication between histone H3 and H4 acetylation and Akt‐mTOR signalling in prostate cancer cells

Makarević

Tawanaie

Juengel

et al. 2014

J Cellular Molecular Medi

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Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTORhigh, aH3/aH4low) and tumour-suppressing signals (Akt/mTORlow, aH3/aH4high) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTORhigh) or mTOR inhibitor (aH3/aH4low) alone.

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Section: Discussionmentioning

confidence: 71%

Cross‐communication between histone H3 and H4 acetylation and Akt‐mTOR signalling in prostate cancer cells

Makarević

Tawanaie

Juengel

et al. 2014

J Cellular Molecular Medi

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“…Accordingly, IGF-1R was involved in resistance to EGFR-TKI in mutant KRAS NSCLC cells 16,25,37. Moreover, acetylation mechanisms regulated IGF-1R- and PI3K/AKT signaling,38,39 and the combination of an HDAC inhibitor with an EGFR-TKI inhibited AKT signaling in lung and head and neck cancer cells 9,14,16,33. It has also been reported that HDAC and EGFR co-inhibition modulated ErbB receptor levels but that these effects were independent of the EGFR or KRAS status 9,33.…”

Section: Discussionmentioning

confidence: 99%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

OTT

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Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments.

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“…Our data further suggest that the IR is prone to (de)acetylation, and that acetylation of the IR depends on the presence of Afadin. Notably, even though no acetylation site has yet been mapped on the IR, the IGF-1R is acetylated on lysine 1088 [33], which is a highly conserved residue between the IGF-1R and the IR (lysine 1112) [34]. Although we cannot exclude that IGF1-R acetylation is also detected in this IP (as part of a hybrid complex with IR), and/ or that other acetylation events participate in this regulation, our data raise the interesting possibility that IR levels are regulated via acetylation at this specific residue.…”

Section: A Body Weight Bmentioning

confidence: 99%

Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

et al. 2019

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Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine‐tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell‐autonomous and phosphorylation‐dependent manner. Insulin‐stimulated Afadin‐S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue‐specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet‐induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin‐induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.

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Protein acetylation mechanisms in the regulation of insulin and insulin-like growth factor 1 signalling

Cited by 22 publications

References 86 publications

Cross‐communication between histone H3 and H4 acetylation and Akt‐mTOR signalling in prostate cancer cells

Cross‐communication between histone H3 and H4 acetylation and Akt‐mTOR signalling in prostate cancer cells

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Afadin is a scaffold protein repressing insulin action via HDAC 6 in adipose tissue

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