Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF‐Iβ induces p21 transcription

Chae, Yun-Cheol; Kim, Kee-Beom; Kang, Joo-Young; Kim, Se-Ryeon; Jung, Hyeonsoo; Seo, Sang-Beom

doi:10.1016/j.febslet.2014.06.053

Cited by 24 publications

(23 citation statements)

References 22 publications

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“…Since Nir was shown not to be present with HDACs, it is highly possible that Nir is part of an activating complex, where it prevents the acetylation of one of the key transcriptional activation factors, thereby promoting gene transcription, and deacetylation of H3K18 might only be a side effect. This was previously observed for the INHAT SET/TAF-Iβ, which inhibits Foxo1 acetylation and activates its transcriptional activity toward p21 (Chae et al, 2014). Similarly, hyperacetylation of Foxp3, which is regulated by the histone acetyltransferase p300 and the HDAC SIRT1, increases Foxp3 protein stability (van Loosdregt et al, 2010).…”

Section: Discussionsupporting

confidence: 63%

The histone acetyltransferase inhibitor Nir regulates epidermis development

et al. 2018

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In addition to its function as an inhibitor of histone acetyltransferases, Nir (Noc2l) binds to p53 and TAp63 to regulate their activity. Here, we show that epidermis-specific ablation of Nir impairs epidermal stratification and barrier function, resulting in perinatal lethality. Nir-deficient epidermis lacks appendages and remains single layered during embryogenesis. Cell proliferation is inhibited, whereas apoptosis and p53 acetylation are increased, indicating that Nir is controlling cell proliferation by limiting p53 acetylation. Transcriptome analysis revealed that Nir regulates the expression of essential factors in epidermis development, such as keratins, integrins and laminins. Furthermore, Nir binds to and controls the expression of and limits H3K18ac at the promoter. Corroborating the stratification defects, asymmetric cell divisions were virtually absent in Nir-deficient mice, suggesting that Nir is required for correct mitotic spindle orientation. In summary, our data define Nir as a key regulator of skin development.

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Section: Discussionsupporting

confidence: 63%

The histone acetyltransferase inhibitor Nir regulates epidermis development

et al. 2018

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“…SET is mostly located in the nucleus where it regulates DNA replication, chromatin remodeling, gene transcription 20 , DNA repair 21 , migration 22 , and cell-cycle progression 23 . Here, we report a robust accumulation of SET into the cytoplasm of primary and patient-derived AML cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, targeting SET allows PP2A to be reactivated indirectly, avoiding toxicity problems related to the direct activation of this complex holoenzyme. SET is a multitask oncogenic protein involved in many cellular processes [20][21][22][23] . However, despite the prognostic impact of SET overexpression in both hematologic and solid tumors, the mechanisms by which SET is regulated remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38β is a common event in AML. We provide evidence that p38β potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38β/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.

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“…Previous studies showed that SET also regulates the activities of several other cellular factors, including histone H3, KU70 and FOXO1, through direct interactions 21-23 . Notably, the binding regions of all three proteins contain a lysine-rich domain (KRD) similar to the CTD of p53 (Fig.…”

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confidence: 99%

Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode

Wang

Kon

Lasso

et al. 2016

Nature

163

160

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Summary Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins1-3, the mechanisms of acetylation mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 was the first example for non-histone protein acetylation4. Yet the precise role of the CTD acetylation remains elusive. Lysine acetylation often creates binding sites for bromodomain-containing “reader” proteins5,6; surprisingly, in a proteomic screen, we identified SET as a major cellular factor whose binding with p53 is totally dependent on the CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells but SET-mediated repression is completely abolished by stress-induced p53 CTD acetylation. Moreover, loss of the interaction with SET activates p53, resulting in tumor regression in mouse xenograft models. Notably, the acidic domain of SET acts as a “reader” for unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, p53 acetylation also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP, DAXX and PELP1 (refs. 7-9), and computational analysis of the proteome identified numerous proteins with the potential to serve as the acidic domain readers and lysine-rich ligands. Unlike bromodomain readers, which preferentially bind the acetylated forms of their cognate ligands, the acidic domain readers specifically recognize the unacetylated forms of their ligands. Finally, the acetylation-dependent regulation of p53 was further validated in vivo by using a knockin mouse model expressing an acetylation-mimicking form of p53. These results reveal that the acidic domain-containing factors act as a new class of acetylation-dependent regulators by targeting p53 and potentially, beyond.

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Inhibition of FoxO1 acetylation by INHAT subunit SET/TAF‐Iβ induces p21 transcription

Cited by 24 publications

References 22 publications

The histone acetyltransferase inhibitor Nir regulates epidermis development

The histone acetyltransferase inhibitor Nir regulates epidermis development

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode

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