EZH2‐mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARγ

Du, Zhipeng; Liu, Mei; Wang, Zhihui; Lin, Zhuoying; Feng, Yangyang; Tian, Dean; Xia, Limin

doi:10.1111/cpr.13072

Cited by 24 publications

(16 citation statements)

References 52 publications

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“…We provided strong evidence of fibrotic lesions, inflammatory infiltration, and cell degeneration in the heart, liver, and kidney of KLF14 −/− mice, which is likely due to the low KLF14 and POLD1 levels in the tissues. Moreover, recently reported findings revealed that KLF14 exerted a protective role in cardiovascular disease and multiple chronic liver diseases by inhibiting inflammation and fibrosis, which is consistent with our results 63 . Furthermore, we found atrophy in the spleen of KLF14 −/− mice with low KLF14 and POLD1 expression compared with WT mice.…”

Section: Discussionsupporting

confidence: 93%

Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

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Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether KLF14 is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the serum and lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6 mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in SAMP8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14’s transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

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Section: Discussionsupporting

confidence: 93%

Downregulation of KLF14 accelerated cellular senescence and aging

Hou¹,

Qiao²,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…This process was accompanied by the downregulation of H3K9me3 and upregulation of H3K4me3 in the promoter region of PPARγ2 ( Erener et al, 2012 ), suggesting that PARP may be involved in regulating adipocyte differentiation by affecting epigenetic modifications. In line with this phenomenon, EZH2 coincides with the ability to catalyze histone methylation in the promoter region of PPARγ2, the result of which promotes processes such as liver fibrosis ( Du et al, 2021 ) and pancreatic cancer cell proliferation ( Hu et al, 2021 ). Interestingly, our previous research has also found EZH2 inhibitor GSK126 upregulates the expression level of fatty acid synthesis related genes and results in lipid droplet accumulation in liver ( Zhang et al, 2022 ).…”

Section: Association Between Ezh2 and Poly Adp-ribose Polymerase In T...mentioning

confidence: 76%

Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges

et al. 2022

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Tumors with BRCA1/2 mutations or homologous recombination repair defects are sensitive to PARP inhibitors through the mechanism of synthetic lethality. Several PARP inhibitors are currently approved for ovarian, breast and pancreatic cancer in clinical practice. However, more than 40% of patients with BRCA1/2 mutations are insensitive to PARP inhibitors, which has aroused attention to the mechanism of PARP resistance and sensitization schemes. PARP inhibitor resistance is related to homologous recombination repair, stability of DNA replication forks, PARylation and epigenetic modification. Studies on epigenetics have become the hotspots of research on PARP inhibitor resistance. As an important epigenetic regulator of transcription mediated by histone methylation, EZH2 interacts with PARP through DNA homologous recombination, DNA replication, posttranslational modification, tumor immunity and other aspects. EZH2 inhibitors have been just shifting from the bench to the bedside, but the combination scheme in cancer therapy has not been fully explored yet. Recently, a revolutionary drug design combining PARP inhibitors and EZH2 inhibitors based on PROTAC techniques has shed light on the resolution of PARP inhibitor resistance. This review summarizes the interactions between EZH2 and PARP, suggests the potential PARP inhibitor sensitization effect of EZH2 inhibitors, and further discusses the potential populations that benefit from the combination of EZH2 inhibitors and PARP inhibitors.

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“…Perugorria et al demonstrated that histone methyltransferase ASH1, as a key transcriptional active component in the MeCP2 regulatory pathway, jointly regulates the expression of multiple fibrosis-related genes (CFTR and PPARs) and ultimately stimulates liver fibrosis. 25,26 Except that histone methylation may be the "cause" of the progress of liver fibrosis, the changes in the microenvironment during the progress of liver fibrosis can also result in abnormal regulation of histone methylation. For example, alcohol intake in alcoholic liver disease causes the trimethylation of the histone H3K4 (H3K4me3) of HSC.…”

Section: Antagonizing Ezh2 Can Synergistically Inhibit Hepatic Stella...mentioning

confidence: 99%

Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti‐fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells

Jia

Chen

Wang

et al. 2023

J of Gastro and Hepatol

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Background and Aim Whether vitamin D3 (VD3) supplementation is associated with improved liver fibrosis is controversial. Methods Liver fibrosis models were treated with VD3, active VD (1,25‐OH2 Vitamin D3), or collaboration with GSK126 (Ezh2 inhibitor), respectively. Hepatic stellate cells (HSCs) were co‐cultured with hepatocytes and then stimulated with TGF‐β. Autophagy of hepatocytes was determined after the intervention of 1,25‐OH2 Vitamin D3 and GSK126. Also, the active status of HSCs and the mechanism with 1,25‐OH2 Vitamin D3 and GSK126 intervention were detected. Results 1,25‐OH2 Vitamin D3, but not VD3, is involved in anti‐fibrosis and partially improves liver function, which might be associated with related enzymes and receptors (especially CYP2R1), leading to decreased of its biotransformation. GSK126 plays a synergistic role in anti‐fibrosis. The co‐culture system showed increased hepatocyte autophagy after HSCs activation. Supplementation with 1,25‐OH2 Vitamin D3 or combined GSK126 reduced these effects. Further studies showed that 1,25‐OH2 Vitamin D3 promoted H3K27 methylation of DKK1 promoter through VDR/Ezh2 due to the weakening for HSCs inhibitory signal. Conclusions VD3 bioactive form 1,25‐OH2 Vitamin D3 is responsible for the anti‐fibrosis, which might have bidirectional effects on HSCs by regulating histone modification. The inhibitor of Ezh2 plays a synergistic role in this process.

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EZH2‐mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARγ

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 24 publications

References 52 publications

Downregulation of KLF14 accelerated cellular senescence and aging

Downregulation of KLF14 accelerated cellular senescence and aging

Combined inhibition of PARP and EZH2 for cancer treatment: Current status, opportunities, and challenges

Antagonizing EZH2 combined with vitamin D3 exerts a synergistic role in anti‐fibrosis through bidirectional effects on hepatocytes and hepatic stellate cells

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