Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

Wakabayashi, Yu; Tamiya, Taiga; Takada, Ichiro; Fukaya, Takao; Sugiyama, Yuki; Inoue, N.; Kimura, Akihiro; Morita, Rimpei; Kashiwagi, Ikko; Takimoto, Tetsuya; Nomura, Masatoshi; Yoshimura, Akihiko

doi:10.1074/jbc.m111.236794

Cited by 41 publications

(37 citation statements)

References 39 publications

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“…Recently, Chou and colleagues proposed a model in ovarian cancer involving TGFb/SMAD4 signaling-mediated epigenetic silencing that results in changes in various associated histone modification, which, in turn, affects the epithelial-to-mesenchymal transition (44). Another study showed that SMAD3 also interacts with a KMT that is recruited to a target locus and that represses gene expression (45). Here, we determined that KMT1E physically interacts with SMAD2/3 in vivo (Fig.…”

Section: Discussionmentioning

confidence: 61%

H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

Wu¹,

Yang

et al. 2014

Cancer Research

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Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells. Restoring KMT1E expression in this setting suppressed filopodia formation, migration, and invasive behavior. Conversely, loss of KMT1E in lung cancer cells with limited metastatic potential promoted migration in vitro and restored metastatic prowess in vivo. Mechanistic investigations indicated that KMT1E cooperates with the TGFb-regulated complex SMAD2/3 to repress metastasis through ANXA2. Together, our findings defined an essential role for the KMT1E/ SMAD2/3 repressor complex in TGFb-mediated lung cancer metastasis. Cancer Res; 74(24); 7333-43. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 61%

H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

Wu¹,

Yang

et al. 2014

Cancer Research

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“…In T cells, we have shown that most of the TGF-b-induced or -repressed genes are redundantly regulated by Smad2 and Smad3 (Takimoto et al, 2010). For example, Smad2 and Smad3 are redundantly essential for Foxp3 induction (Takimoto et al, 2010), IL-9 expression (Tamiya et al, 2013), and IL-2 suppression (Wakabayashi et al, 2011) by TGF-b in T cells. Similarly, both Smad2 and Smad3 are important for the suppression of Nos2 expression in macrophages (Sugiyama et al, 2012).…”

Section: Discussionmentioning

confidence: 95%

Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells

et al. 2015

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Colonization with a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-β (TGF-β) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-β remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum (C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-β1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-β1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-β-Smad3 transcription factor signal was necessary for robust TGF-β expression in DCs, whereas Smad2 negatively regulated TGF-β expression. Smad2-deficient DCs expressed higher concentrations of TGF-β and were tolerogenic for colitis models. This study reveals a novel mechanism of TGF-β induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-β-Smad signaling pathways.

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“…In addition, a recent study has reported that TGF-b1 suppresses IL-2 production from T cells through H3K9me3, but not H3K4me1. 35 These findings raise the possibility that inhibition of H3K4me1 is a novel and attractive therapeutic strategy for treating renal fibrosis. In summary, SET7/9 expression is regulated by the TGFb1-Smad3 pathway, leading to transcriptional activation of fibrotic genes through increased H3K4me1.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

Sasaki

Doi

Nakashima

et al. 2016

Journal of the American Society of Nephrology

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TGF-b1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-b1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-b1 neutralizing antibody. TGF-b1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P,0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-b1-induced a-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.

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Histone 3 Lysine 9 (H3K9) Methyltransferase Recruitment to the Interleukin-2 (IL-2) Promoter Is a Mechanism of Suppression of IL-2 Transcription by the Transforming Growth Factor-β-Smad Pathway

Cited by 41 publications

References 39 publications

H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis

Smad2 and Smad3 Inversely Regulate TGF-β Autoinduction in Clostridium butyricum-Activated Dendritic Cells

Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis

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