Brg1 promotes liver regeneration after partial hepatectomy via regulation of cell cycle

Wang, Baocai; Kaufmann, Benedikt; Engleitner, Thomas; Miao, Liyun; Mogler, Carolin; Olsavszky, Victor; Öllinger, Rupert; Zhong, Suyang; Géraud, Cyrill; Cheng, Zhao; Rad, Roland; Schmid, Roland M.; Friess, Helmut; Hüser, Norbert; Figura, Guido von

doi:10.1038/s41598-019-38568-w

Cited by 26 publications

(18 citation statements)

References 37 publications

(39 reference statements)

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“…3c). Consistent with a previous report 21 , we found that loss of Brg1 did not affect liver homeostasis: indeed, liver/body weight ratio ( Fig. 3d), liver histology as well as hepatocyte proliferation (Fig.…”

Section: Loss Of Brg1 Does Not Affect Liver Homeostasissupporting

confidence: 93%

Oncogene-dependent function of BRG1 in hepatocarcinogenesis

et al. 2020

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Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Genomic studies have revealed that HCC is a heterogeneous disease with multiple subtypes. BRG1, encoded by the SMARCA4 gene, is a key component of SWI/SNF chromatin-remodeling complexes. Based on TCGA studies, somatic mutations of SMARCA4 occur in~3% of human HCC samples. Additional studies suggest that BRG1 is overexpressed in human HCC specimens and may promote HCC growth and invasion. However, the precise functional roles of BRG1 in HCC remain poorly delineated. Here, we analyzed BRG1 in human HCC samples as well as in mouse models. We found that BRG1 is overexpressed in most of human HCC samples, especially in those associated with poorer prognosis. BRG1 expression levels positively correlate with cell cycle and negatively with metabolic pathways in the Cancer Genome Atlas (TCGA) human HCC data set. In a murine HCC model induced by c-MYC overexpression, ablation of the Brg1 gene completely repressed HCC formation. In striking contrast, however, we discovered that concomitant deletion of Brg1 and overexpression of c-Met or mutant NRas (NRAS V12) triggered HCC formation in mice. Altogether, the present data indicate that BRG1 possesses both oncogenic and tumor-suppressing roles depending on the oncogenic stimuli during hepatocarcinogenesis.

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Section: Loss Of Brg1 Does Not Affect Liver Homeostasissupporting

confidence: 93%

Oncogene-dependent function of BRG1 in hepatocarcinogenesis

et al. 2020

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“…A follow-up study by Weng and colleagues have found that the long non-coding RNA LncFZD6 recruits BRG1 to the Frizzled6 promoter and the Wnt5a promoter to activate transcription, thereby driving liver cancer cell self-renewal ( Chen et al, 2018 ). More recently, Li N. et al (2019) and Wang et al (2019) have independently reported that BRG1 deficiency cripples liver regenerative response in mice accompanying down-regulation of β-catenin target genes related to cell proliferation. In light of our new data as summarized here, it is tempting to propose that BRG1 may be an integral part of the Wnt/β-catenin pathway functioning at several different levels (upstream and downstream of β-catenin) to amplify the signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

Sun

Chen

et al. 2020

Front. Cell Dev. Biol.

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A disintegrin and metalloproteinase (ADAM) family of proteins play versatile roles in cancer development and progression. In the present study, we investigated the role of ADAM proteins in colorectal cancer (CRC) cell migration and invasion focusing on the epigenetic mechanism whereby ADAM transcription is regulated. We report that higher levels of ADAM10, ADAM17, and ADAM19 were detected in SW480 cells than in HCT116 cells. Expression levels of the same set of ADAMs were higher in human CRC biopsy specimens of advanced stages than in those of a less aggressive phenotype. Overexpression of ADAM10/17/19 in HCT116 cells enhanced, whereas depletion of ADAM10/17/19 in SW480 cells weakened, migration and invasion. ADAM expression was activated by the Wnt signaling pathway, which could be attributed to direct binding of β-catenin on the ADAM promoters. Mechanistically, β-catenin recruited the chromatin remodeling protein BRG1, which in turn enlisted histone demethylase KDM4 to alter the chromatin structure, thereby leading to ADAM transactivation. In conclusion, our data suggest that the Wnt signaling may promote CRC metastasis, at least in part, by recruiting an epigenetic complex to activate ADAM transcription.

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“…It should be noted that liver-specific deletion of β-catenin appears to render the mice more susceptible to the development of steatosis ( Behari et al, 2010 ) and HCC ( Wang et al, 2011 ), suggesting that any benefit of targeting β-catenin in the intervention of FH has to be weighed against its potential risks. We and others have previously shown that β-catenin relies on BRG1 to regulate the transcription of pro-proliferative genes in hepatocytes and to promote liver regeneration ( Li et al, 2019a ; Wang et al, 2019 ). Of note, multiple independent studies have implicated nephronectin in the regulation of cellular proliferation.…”

Section: Discussionmentioning

confidence: 99%

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

Hong

Kong²,

et al. 2021

Front. Cell Dev. Biol.

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Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.

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Brg1 promotes liver regeneration after partial hepatectomy via regulation of cell cycle

Cited by 26 publications

References 37 publications

Oncogene-dependent function of BRG1 in hepatocarcinogenesis

Oncogene-dependent function of BRG1 in hepatocarcinogenesis

Epigenetic Regulation of a Disintegrin and Metalloproteinase (ADAM) Transcription in Colorectal Cancer Cells: Involvement of β-Catenin, BRG1, and KDM4

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

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