Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Tang, Bo; Qi, Guangying; Tang, Fang; Yuan, Shengguang; Wang, Zhenran; Liang, Xingsi; Li, Bo; Yu, Shuiping; Liu, Jie; Huang, Qi; Wei, Yangchao; Zhai, Run; Lei, Biao; Yu, Hongping; Tomlinson, Stephen; He, Songqing

doi:10.1158/0008-5472.can-15-3029

Cited by 81 publications

(58 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, recent studies have highlighted the importance of JmjC domain-containing proteins in the regulation of EMT, which is an underlying mechanism for tumor invasion and metastasis (25)(26)(27)(28)(29)(30)(31). One member of this protein family, Jumonji domain-containing protein 2B (JMJD2B, also known as KDM4B) transcriptionally activates gene expression by demethylation of the repressive histone mark H3K9me3 and further coordinates the methylation of the activating histone mark H3K4me3 (32)(33)(34).…”

Section: Significancementioning

confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.

show abstract

Section: Significancementioning

confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Furthermore, it has been shown that Snail2 promotes tumor invasion . JMJD3 upregulates Snail2 to promote migration and invasion in HCC . However, the mechanism through which Snail2 controls E‐cadherin silencing in malignant carcinomas remains undefined.…”

Section: Discussionmentioning

confidence: 99%

“…45 JMJD3 upregulates Snail2 to promote migration and invasion in HCC. 46 However, the mechanism through which Snail2 controls E-cadherin silencing in malignant carcinomas remains undefined. In the present study, we first confirmed the importance of Snail2 in EMT in malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

Zheng

Dai

et al. 2019

Cancer Science

View full text Add to dashboard Cite

Functional E‐cadherin loss, a hallmark of epithelial‐mesenchymal transition (EMT), is important for metastasis. However, the mechanism of Snail2 in hepatocellular carcinoma (HCC) EMT and metastasis remains unclear. Here, we showed that Snail2 was upregulated in primary HCC, and significantly increased during transforming growth factor‐β‐induced liver cell EMT. Snail2‐overexpressing and knockdown cell lines have been established to determine its function in EMT in HCC. H3K9 methylation was upregulated and H3K4 and H3K56 acetylation were downregulated at the E‐cadherin promoter in Snail2‐overexpressing cancer cells. Furthermore, Snail2 interacted with G9a and histone deacetylases (HDACs) to form a complex to suppress E‐cadherin transcription. Snail2 overexpression enhanced migration and invasion in HCC cells, whereas G9a and HDAC inhibition significantly reversed this effect. Moreover, Snail2 overexpression in cancer cells increased tumor metastasis and shortened survival time in mice, whereas G9a and HDAC inhibitors extended survival. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also suggests novel treatment strategies for HCC.

show abstract

“…CSNK2A2, FRA1, ACTB, SLUG, and VEGFB are believed to be involved in invasion/migration (42,43). Their expressions were significantly lower in CAY10591-treated cells than in vehicle-treated cells (Fig.…”

Section: Cay10591 Suppresses Expression Of Cell Invasion/ Migration Gmentioning

confidence: 94%

CAY10591, a SIRT1 activator, suppresses cell growth, invasion, and migration in gingival epithelial carcinoma cells

et al. 2017

View full text Add to dashboard Cite

SIRT1 is a NAD-dependent histonedeacetylase that is important in a wide variety of physiological and pathophysiological processes. Although many studies have examined the relationship between SIRT1 and cancer, the role of SIRT1 in tumor malignancy is controversial. Here, we examined the effects of the SIRT1 activator CAY10591 in gingival epithelial carcinoma Ca9-22 cells. CAY10591 treatment dose-and time-dependently increased SIRT1 level and activity. The treatment decreased cell growth and induced cell-cycle repressor p21 levels. In addition, dimethyl sulfoxide significantly reduced cellular invasion and migration, and CAY10591 enhanced this decrease. Quantitative PCR analysis showed that CAY10591 decreased expression of several invasion/ migration promoter genes and induced repressor genes. Our findings suggest that CAY10591 suppresses cell growth and invasion/migration activity in gingival squamous cell carcinoma Ca9-22 cells.

show abstract

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell–Like Behaviors in Hepatocellular Carcinoma

Cited by 81 publications

References 23 publications

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

CAY10591, a SIRT1 activator, suppresses cell growth, invasion, and migration in gingival epithelial carcinoma cells

Contact Info

Product

Resources

About