Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration

Russell, Jacquelyn O.; Ko, Sungjin; Saggi, Harvinder; Singh, Sucha; Poddar, Minakshi; Shin, Donghun; Monga, Satdarshan P.

doi:10.1016/j.ajpath.2018.02.006

Cited by 12 publications

(11 citation statements)

References 71 publications

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“…A recent study showed that BET protein inhibition inhibits liver regeneration by inhibiting the Wnt signaling pathway 38. Our data demonstrate that the BET proteins inhibition affect the liver regeneration by inhibiting the YAP/TAZ-Notch1-NICD axis, and uncovered the role of YAP/TAZ-Notch1-NICD in liver regeneration.…”

Section: Discussionsupporting

confidence: 57%

Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration

et al. 2019

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Background and aims : Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. Methods : We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro . We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo . Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. Results : In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro . By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo . Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. Conclusion : These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.

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Section: Discussionsupporting

confidence: 57%

Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration

et al. 2019

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“…They mediate different steps of BEC-driven regeneration in zebrafish, BEC dedifferentiation into LPC, proliferation of LPC and redifferentiation into new hepatocytes and their maturation [ 28 ]. In addition, BET proteins also promote hepatocyte-driven liver regeneration in a zebrafish liver injury model of paracetamol (APAP) overdose ( Table 1 ) [ 26 ]. Importantly, the requirement for BET proteins in both types of liver regeneration is conserved in mice.…”

Section: Awakening the Regenerative Capacity In Different Organsmentioning

confidence: 99%

“…In the choline-deficient ethionine-supplemented CDE-diet mouse model of chronic liver injury that induces BEC-driven regeneration, BET proteins are required for activation of LPC [ 28 ]. In mice after partial hepatectomy, BET proteins are required for hepatocyte proliferation [ 26 ]. These data are of high clinical relevance as the same BET inhibitor, JQ1, has been used in a clinical trial for cancer therapy, including liver cancer.…”

Section: Awakening the Regenerative Capacity In Different Organsmentioning

confidence: 99%

“…These data are of high clinical relevance as the same BET inhibitor, JQ1, has been used in a clinical trial for cancer therapy, including liver cancer. The authors stressed that, even though such drugs could be beneficial in this specific context, they would also inhibit liver regeneration, thereby limiting their therapeutic use [ 26 ]. Given the importance of BET proteins as epigenetic regulators, a second chemical screen with a library of compounds targeting epigenetic factors has been conducted with the same zebrafish NTR-mediated liver ablation model [ 29 ].…”

Section: Awakening the Regenerative Capacity In Different Organsmentioning

confidence: 99%

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Zebra-Fishing for Regenerative Awakening in Mammals

2021

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Regeneration is defined as the ability to regrow an organ or a tissue destroyed by degeneration or injury. Many human degenerative diseases and pathologies, currently incurable, could be cured if functional tissues or cells could be restored. Unfortunately, humans and more generally mammals have limited regenerative capabilities, capacities that are even further declining with age, contrary to simpler organisms. Initially thought to be lost during evolution, several studies have revealed that regenerative mechanisms are still present in mammals but are latent and thus they could be stimulated. To do so there is a pressing need to identify the fundamental mechanisms of regeneration in species able to efficiently regenerate. Thanks to its ability to regenerate most of its organs and tissues, the zebrafish has become a powerful model organism in regenerative biology and has recently engendered a number of studies attesting the validity of awakening the regenerative potential in mammals. In this review we highlight studies, particularly in the liver, pancreas, retina, heart, brain and spinal cord, which have identified conserved regenerative molecular events that proved to be beneficial to restore murine and even human cells and which helped clarify the real clinical translation potential of zebrafish research to mammals.

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“…Bromodomains of bromodomain and extraterminal (BET) proteins, which regulate transcription by binding to acetylated lysine residues on histone tails, also regulate hepatocellular proliferation in hepatocyte-driven liver regeneration [116] . Russell et al [116] have shown that the drug JQ1, a specific inhibitor of Brd4 (one of BET proteins), impairs hepatocyte proliferation in partial hepatectomy and acetaminophen-induced liver regeneration with significant reduction in E2f2 genes and cyclin-D1.…”

Section: Epigenetic Regulation Of Liver Regenerationmentioning

confidence: 99%

Liver regeneration: metabolic and epigenetic regulation

Verma¹,

Purohit²,

Arora³

et al. 2021

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The liver is bestowed with an extraordinary regenerative capability, which is accomplished by a well-coordinated cellular and molecular response at different phases of regeneration. Metabolism, as the primary function of liver, displays various alterations as a consequence of hepatic insufficiency from an injury. These metabolic perturbations are physiologically relevant for promoting hepatocellular proliferation and regeneration. On the other hand, proliferation of otherwise quiescent hepatocytes and accompanied regeneration are regulated by transient, but precisely regulated transcriptional reprogramming. This phase-cell-and time-specific gene expression is controlled by epigenetic mechanisms. Hence, both metabolic and epigenetic changes regulate liver regeneration events. But the cross-talk between metabolic and epigenetic changes for a successful liver regeneration needs to be explored. Since most of the enzymatic players of epigenetic mechanisms rely upon metabolites for their substrates and co-factors, we expect a highly coordinated interdependence between metabolism and epigenetics during liver regeneration too. In the present review, we discuss various metabolic and epigenetic regulatory mechanisms for liver regeneration, and put forward the possible metabolic-epigeneticliver regeneration link for a better understanding of the process and identification of novel targets for liver-related diseases in clinical settings.

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Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration

Cited by 12 publications

References 71 publications

Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration

Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration

Zebra-Fishing for Regenerative Awakening in Mammals

Liver regeneration: metabolic and epigenetic regulation

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