Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Wu, Yuting; Bu, Fang-tian; Hou, Yu; Li, Wanxia; Huang, Cheng; Meng, Xiao‐Ming; Zhang, Lei; Ma, Tao; Li, Jun

doi:10.1016/j.taap.2016.12.002

Cited by 43 publications

(34 citation statements)

References 78 publications

(83 reference statements)

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“…Furthermore, different septin members might have different biological function. It has been reported that SEPT4 and SEPT9 were remarkably downregulated in HSC activation and liver fibrosis; loss-of-SEPT4 exacerbated liver fibrosis [26], and SEPT9 contributed to alleviate liver fibrosis partially through promoting activated HSCs apoptosis [27]. Taken together, we demonstrated for the first time that SEPT6 promotes HSCs activation, proliferation, cell cycle progression, migration, and survival, likely by activating the TGF-β1/Smad, MAPK, and PI3K/AKT signaling pathways.…”

Section: Discussionsupporting

confidence: 52%

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Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism

Fan

Steib³

et al. 2019

Laboratory Investigation

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Hepatic stellate cells (HSCs) are key effectors during the development of liver fibrosis. Septin 6 (SEPT6) is a highly evolutionarily conserved GTP-binding protein that regulates various cell biological behaviors. The expression and function of SEPT6 in HSCs remain unknown. Here we demonstrate that SEPT6 expression is significantly elevated following the activation of primary rat HSCs, the human hepatic stellate cell line LX-2 and the rat hepatic stellate cell line HSC-T6, as well as in both human and rat fibrotic liver tissue. In vitro, the overexpression of SEPT6 promoted HSCs activation, proliferation, cell cycle progression and migration and inhibited HSCs apoptosis. In contrast, knockdown of SEPT6 exerted the opposite effects on HSCs. Mechanistically, SEPT6 exerted its pro-fibrogenic effect by promoting the expression of TGF-β1 and the phosphorylation of Smad2, Smad3, extracellular-signal-regulated kinase, c-Jun NH2-terminal kinase, stress-activated protein kinase-2, and protein kinase B. However, in HSC-T6 cells, blockade of the TGF-β1/Smad signaling pathway by SB431542 significantly decreased the expression of α-smooth muscle actin, cyclin D1, BCL2, and matrix metalloproteinase-2 and-9, which had been enhanced by SEPT6 overexpression. In vivo, adenovirus-mediated SEPT6 inhibition attenuated thioacetamide (TAA)-induced liver fibrosis in rats by decreasing the deposition of the extracellular matrix (ECM). SEPT6 inhibition decreased the proliferation capacity of HSCs and induced apoptosis of HSCs. Collectively, our results reveal that SEPT6 regulates various biological behaviors in HSCs through TGF-β1/Smad, mitogen-activated protein kinases and phosphatidylinositol-3-kinase/protein kinase B signaling pathways, thus promoting liver fibrosis.

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Section: Discussionsupporting

confidence: 52%

“…This finding implies that SEPT6 plays tissue-specific roles. SEPT4 and SEPT9 have been shown to be decreased following HSCs activation, and the loss of SEPT4 and SEPT9 exacerbates liver fibrosis [26,27]. We detect the level of the entire septins member in healthy and fibrotic rat liver and find that the SEPT6 is elevated significantly.…”

Section: Introductionmentioning

confidence: 82%

Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism

Fan

Steib³

et al. 2019

Laboratory Investigation

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“…In addition, TGF‐β1 promoted the expression of DNMT1 and DNMT3A, especially DNMT3A, which suggests that TGF‐β1 plays a certain role in the regulation of EYA4 expression in ESCC. In other human malignancies, TGF‐β1 has also been found to affect transcription and expression of downstream target genes via the regulation of DNMT expression . In ovarian cancer cells, TGF‐β1 induced the expression of DNMT and led to extensive genomic hypermethylation, which influenced the transcription of EMT‐related genes and promoted the EMT process .…”

Section: Discussionmentioning

confidence: 99%

“…In other human malignancies, TGF-b1 has also been found to affect transcription and expression of downstream target genes via the regulation of DNMT expression. [35][36][37] In ovarian cancer cells, TGF-b1 induced the expression of DNMT and led to extensive genomic hypermethylation, which influenced the transcription of EMT-related genes and promoted the EMT process. 38 In hepatocellular carcinoma, TGF-b1 transformed HCC cells into cells with a spindle-shaped morphology, which was accompanied by hypermethylation of CDH1 and the methylation of its promoter.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

Luo

Shi

et al. 2018

Cancer Science

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EYA4, one of the four members of the EYA gene family, is associated with several human cancers. However, its biological functions and molecular mechanisms in the progression of cancer, particularly in esophageal squamous cell carcinoma (ESCC), remain unknown. In the present study, we found that EYA4 was underexpressed and hypermethylated in most of the ESCC cell lines tested (85.7%, 6/7). Treatment with 5‐aza‐dC and/or trichostatin A (TSA) restored EYA4 expression in ESCC cell lines, which indicates that EYA4 expression was epigenetically regulated. Similarly, EYA4 was aberrantly hypermethylated in ESCC tissues (78%, 39/50) and downregulation of EYA4 occurred in approximately 65% of primary ESCC at protein level where it was associated significantly with TNM stage and lymph node metastases. Knockdown of EYA4 in KYSE30 and KYSE70 ESCC cells using small hairpin RNA increased migration and invasive motility in vitro. Conversely, the overexpression of EYA4 in KYSE180 and KYSE450 promoted an epithelial phenotype, which consisted of decreased migration and invasion abilities and a decrease in TGF‐β1‐induced epithelial‐mesenchymal transition. Mechanistically, EYA4 overexpression reduced the phosphorylation of Akt and glycogen synthase kinase (GSK) 3β, which led to the inactivation of slug. In addition, we found that TGF‐β1 decreased EYA4 expression in both a dose‐dependent and a time‐dependent manner in KYSE30 cells, accompanied by an increase in the expression of DNA methyltransferases, especially DNMT3A. In summary, EYA4 is frequently hypermethylated in ESCC and may function as a tumor suppressor gene in the development of ESCC.

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“…Septins are a group of GTPase proteins that play a role in cytoskeleton organisation through their links with microtubules and actin filaments (78). Although some septins are associated with the advancement of kidney fibrosis (78), SEPTIN9 specifically has been implicated in a host of disease pathologies, such as prostate cancer (79), colorectal cancer (80), liver fibrosis (81) and T2DM (82). Moreover, SEPTIN9 overexpression has been shown to promote kidney epithelial cell migration (83).…”

Section: Discussionmentioning

confidence: 99%

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

Smyth

Kilner

Nair

et al. 2020

Preprint

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A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), which is the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n=862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p≤x10-8 and fold change ±2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by in silico functional data, and replication where possible, include; AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9, and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals, has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

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Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis

Cited by 43 publications

References 78 publications

Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism

Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism

Aberrant methylation of EYA4 promotes epithelial‐mesenchymal transition in esophageal squamous cell carcinoma

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

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