P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells Into Tumor-Promoting Myofibroblasts

Dou, Changwei; Liu, Zhikui; Tu, Kangsheng; Zhang, Hongbin; Chen, Chen; Yaqoob, Usman; Wang, Yuanguo; Wen, Jialing; Deursen, Jan van; Sicard, Delphine; Tschumperlin, Daniel J.; Zou, Hongzhi; Huang, Wei; Urrutia, Raúl; Shah, Vijay H.; Kang, Ningling

doi:10.1053/j.gastro.2018.02.015

Cited by 158 publications

(155 citation statements)

References 51 publications

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“…E,F) and genetically modified AMPKα1/α2 MEFs showed a clear association between different v‐ATPase subunits and specific AMPKα subunits. Furthermore, cells were treated with the AMPK allosteric, direct activators A769662 and ZLN024, both known to inhibit dephosphorylation of phosphorylated AMPK, and diflunisal, a salicylic acid derivative with analgesic and anti‐inflammatory effects, which has been shown to be a strong CBP/p300 inhibitor and very recently demonstrated to be key in activation of hHSCs . We demonstrate that both diflunisal and A769662 reduce v‐ATPase expression, while ZLN024 had no effect.…”

Section: Discussionmentioning

confidence: 78%

“…Furthermore, cells were treated with the AMPK allosteric, direct activators A769662 (23) and ZLN024, (24) both known to inhibit dephosphorylation of phosphorylated AMPK, and diflunisal, a salicylic acid derivative with analgesic and anti-inflammatory effects, which has been shown to be a strong CBP/p300 inhibitor (25,26) and very recently demonstrated to be key in activation of hHSCs. (35) 11 1150 We demonstrate that both diflunisal and A769662 reduce v-ATPase expression, while ZLN024 had no effect. In addition, diflunisal down-regulates hHSC activation markers in a manner similar to what has been observed in hHSCs treated with the v-ATPase inhibitor bafilomycin.…”

Section: Discussionmentioning

confidence: 80%

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The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

Marrone¹,

Chiara

Böttcher³

et al. 2018

Hepatology

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 80%

The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

Marrone¹,

Chiara

Böttcher³

et al. 2018

Hepatology

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“…An RNeasy Plus Mini Kit was used to isolate total RNA from cultured HSCs for RNA sequencing (RNA‐seq), as we previously did . Details are found in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Chen

et al. 2019

Hepatol Commun

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Transforming growth factor β (TGFβ) induces hepatic stellate cell (HSC) differentiation into tumor-promoting myofibroblast, although underlying mechanism remains incompletely understood. Focal adhesion kinase (FAK) is activated in response to TGFβ stimulation, so it transmits TGFβ stimulus to extracellular signal-regulated kinase and P38 mitogenactivated protein kinase signaling. However, it is unknown whether FAK can, in return, modulate TGFβ receptors. In this study, we tested whether FAK phosphorylated TGFβ receptor 2 (TGFβR2) and regulated TGFβR2 intracellular trafficking in HSCs. The FAKY397F mutant and PF-573,228 were used to inhibit the kinase activity of FAK, the TGFβR2 protein level was quantitated by immunoblotting, and HSC differentiation into myofibroblast was assessed by expression of HSC activation markers, alpha-smooth muscle actin, fibronectin, or connective tissue growth factor. We found that targeting FAK kinase activity suppressed the TGFβR2 protein level, TGFβ1-induced mothers against decapentaplegic homolog phosphorylation, and myofibroblastic activation of HSCs. At the molecular and cellular level, active FAK (phosphorylated FAK at tyrosine 397) bound to TGFβR2 and kept TGFβR2 at the peripheral plasma membrane of HSCs, and it induced TGFβR2 phosphorylation at tyrosine 336. In contrast, targeting FAK or mutating Y336 to F on TGFβR2 led to lysosomal sorting and degradation of TGFβR2. Using RNA sequencing, we identified that the transcripts of 764 TGFβ target genes were influenced by FAK inhibition, and that through FAK, TGFβ1 stimulated HSCs to produce a panel of tumor-promoting factors, including extracellular matrix remodeling proteins, growth factors and cytokines, and immune checkpoint molecule PD-L1. Functionally, targeting FAK inhibited tumorpromoting effects of HSCs in vitro and in a tumor implantation mouse model. Conclusion: FAK targets TGFβR2 to the plasma membrane and protects TGFβR2 from lysosome-mediated degradation, thereby promoting TGFβ-mediated HSC activation. FAK is a target for suppressing HSC activation and the hepatic tumor microenvironment. (Hepatology Communications 2020;4:268-283).269 express α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF), markers of HSC activation, (4,5) and paracrine factors that promote liver metastatic growth. (6) Understanding how TGFβ signaling events are regulated, such as how TGFβ receptors distribute and traffic in HSCs, will help identify targets to inhibit HSC activation and the metastasis-promoting liver microenvironment.Focal adhesion kinase (FAK) is a 125-kDa nonreceptor tyrosine (Y) kinase. It consists of an N-terminal FERM domain, a middle kinase domain, and a C-terminal FAT domain. (7,8) Inactive FAK exists as an auto-inhibited monomer, and its autophosphorylation at Y397 creates a binding site for SH2 domain of Src, so that Src is recruited to induce phosphorylation of FAK at additional sites, leading to full activation of FAK kinase. (7,8) In addition, FAK functions as a protein scaffold for sign...

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“…Analysis of the ENCODE database revealed C/EBP␤-binding sites in close proximity to sites bound by the transcriptional regulator p300 along the promoters of TGF␤-responsive genes, including procollagen 1␣1 and fibronectin. p300 has been implicated in HSC activation and is a known C/EBP␤-binding partner (29,30). In vivo analysis of p300 protein levels showed increased p300 in mice treated with CCl 4 , but this effect was blocked in mice receiving both CCl 4 and adefovir dipivoxil ( Fig.…”

Section: C/ebp␤ Mediates Hsc Activation Through a Mechanism Involvingmentioning

confidence: 93%

Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation

Liu

Kang

et al. 2019

Journal of Biological Chemistry

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Edited by Eric R. FearonTransforming growth factor ␤ (TGF␤) potently activates hepatic stellate cells (HSCs), which promotes production and secretion of extracellular matrix (ECM) proteins and hepatic fibrogenesis. Increased ECM synthesis and secretion in response to TGF␤ is associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). TGF␤ and UPR signaling pathways are tightly intertwined during HSC activation, but the regulatory mechanism that connects these two pathways is poorly understood. Here, we found that TGF␤ treatment of immortalized HSCs (i.e. LX-2 cells) induces phosphorylation of the UPR sensor inositol-requiring enzyme 1␣ (IRE1␣) in a SMAD2/3-procollagen I-dependent manner. We further show that IRE1␣ mediates HSC activation downstream of TGF␤ and that its role depends on activation of a signaling cascade involving apoptosis signaling kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK). ASK1-JNK signaling promoted phosphorylation of the UPR-associated transcription factor CCAAT/enhancer binding protein ␤ (C/EBP␤), which is crucial for TGF␤-or IRE1␣-mediated LX-2 activation. Pharmacological inhibition of C/EBP␤ expression with the antiviral drug adefovir dipivoxil attenuated TGF␤-mediated activation of LX-2 or primary rat HSCs in vitro and hepatic fibrogenesis in vivo. Finally, we identified a critical relationship between C/EBP␤ and the transcriptional regulator p300 during HSC activation. p300 knockdown disrupted TGF␤-or UPR-induced HSC activation, and pharmacological inhibition of the C/EBP␤-p300 complex decreased TGF␤-induced HSC activation. These results indicate that TGF␤-induced IRE1␣ signaling is critical for HSC activation through a C/EBP␤-p300 -dependent mechanism and suggest C/EBP␤ as a druggable target for managing fibrosis.

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P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells Into Tumor-Promoting Myofibroblasts

Abstract: In studies of mice, we found liver stiffness to activate HSC differentiation into myofibroblasts, which required nuclear accumulation of p300. p300 increases HSC expression of genes that promote metastasis.

Cited by 158 publications

References 51 publications

The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation

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