HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism

Fu, Liang; LiSha, Chen; Yang, Jie; Ye, Ting; Chen, Yingxuan; Fang, Jing‐Yuan

doi:10.1093/carcin/bgs217

Cited by 79 publications

(81 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cancer-associated EMT process involves multiple factors and pathways (26,39). In our experiments, we also found the upregulation of E-cadherin and downregulation of Snail in JMJD2B-depleted gastric cancer cells.…”

Section: Discussionsupporting

confidence: 76%

“…The upregulation of the mesenchymal marker vimentin is significantly associated (18,25,26). Indeed, we found the occupancy of JMJD2B on the vimentin promoter coupled with the accumulation of repressive H3K9me3 on vimentin promoter following JMJD2B depletion.…”

Section: Discussionmentioning

confidence: 63%

“…JMJD2B primarily targets the trimethylated lysine 9 of histone H3 (H3K9) and has been reported to play an important role in many biologic processes such as heterochromatin formation, X-chromosome inactivation, homeotic gene silencing, and transcriptional regulation (14)(15)(16). Recently, increasing studies have revealed an epigenetic role of JMJD2B in stem cells differentiation (17), inflammation (18), and tumorigenesis (19)(20)(21)(22)(23)(24)(25)(26). It is reported that JMJD2B interacts with estrogen receptor a (ERa) and is recruited to ERa target sites, which demethylates H3K9me3 and facilitates transcription of ERresponsive genes including MYB, MYC, and CCND1 to play an important role in the development and progression of breast cancer (22).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

JMJD2B Promotes Epithelial–Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis

Zhao

Zang

et al. 2013

Clinical Cancer Research

102

View full text Add to dashboard Cite

Purpose: This study investigated the role of histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in promoting epithelial-mesenchymal transition (EMT) and underlying molecular mechanisms in the progression of gastric cancer.Experimental Design: The induction of EMT by JMJD2B in gastric cancer cells and its underlying mechanisms were examined by a series of assays. In vivo and in vitro assays were performed to clarify invasive potential of JMJD2B in gastric cancer cells. The expression dynamics of JMJD2B were detected using immunohistochemistry in 101 cases of primary gastric cancer tissues.Results: Inhibition of JMJD2B by specific siRNA suppresses EMT of gastric cancer cells, whereas ectopic expression of JMJD2B induces EMT. Importantly, JMJD2B is physically associated with b-catenin and enhances its nuclear localization and transcriptional activity. JMJD2B, together with b-catenin, binds to the promoter of the b-catenin target gene vimentin to increase its transcription by inducing H3K9 demethylation locally. JMJD2B inhibition attenuates migration and invasion of gastric cancer cells in vitro and metastasis in vivo. The expression of JMJD2B was positively correlated with tumor size (P ¼ 0.017), differentiation status (P ¼ 0.002), tumor invasion (P ¼ 0.045), lymph node metastasis (P ¼ 0.000), distant metastasis (P ¼ 0.024), and tumor-node-metastasis (TNM) stage (P ¼ 0.002) in patients with gastric cancer.Conclusions: The data reveal a novel function of JMJD2B in promoting EMT and gastric cancer invasion and metastasis, implicating JMJD2B as a potential target for reversing EMT and intervention of the progression of gastric cancer.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

JMJD2B Promotes Epithelial–Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis

Zhao

Zang

et al. 2013

Clinical Cancer Research

102

View full text Add to dashboard Cite

show abstract

“…Recently, it was reported that KDM4B is involved in the stimulation of hypoxia-inducible genes in colon cancer (64). Possibly, this may involve complex formation of KDM4B with the hypoxia-inducible factor 1α, the master mediator of the hypoxic response, since a relative of KDM4B, the KDM4C protein, can actually bind to hypoxia-inducible factor 1α (65).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase

Berry

Kim

Janknecht

2014

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. The linchpin of colorectal cancer is the oncoprotein and transcriptional cofactor β-catenin, whose overexpression is causative for the neoplastic transformation of colon cells. However, the molecular details of β-catenin dependent gene transcription in cancer cells are still not comprehensively explored. Here, we show that the histone demethylase KDM4B was upregulated in colon and rectal adenocarcinomas and required for efficient growth and clonogenic activity of human HT-29 colon cancer cells. Moreover, KDM4B formed complexes with β-catenin in vitro and in vivo, which involved its central amino acids 353-740. In addition, KDM4B also interacted with the DNA-binding protein TCF4, which is the main factor recruiting β-catenin to chromatin in the intestine. KDM4B downregulation resulted in reduced expression of the β-catenin/TCF4 target genes JUN, MYC and Cyclin D1, all of which encode for oncoproteins. Collectively, our data indicate that KDM4B overexpression supports β-catenin mediated gene transcription and thereby contributes to the genesis of colorectal tumors. Accordingly, inhibition of the KDM4B histone demethylase may represent a novel avenue of fighting colorectal cancer, one of the major causes of cancer death throughout the world. IntroductionColorectal cancer is a major health issue and over 50,000 US residents alone are expected to die from this disease this year (1). A crucial defect in the vast majority of colorectal tumors is the overexpression of the oncoprotein β-catenin. This is primarily due to the loss of the tumor suppressor adenomatous polyposis coli (APC), which normally directs the intracellular destruction of β-catenin, or activating mutations in β-catenin itself (2). Unfortunately, knowledge on the devastating impact of these genetic mutations has not yet translated into improved therapy.Aside from genetic mutations, epigenetic changes are an underlying cause of tumorigenesis. Most prominently, such epigenetic changes involve the methylation of DNA on cytosine residues and the modification of histones by acetylation and methylation (3,4). In contrast to DNA methylation and histone acetylation, the methylation of histones was only recently validated as a major epigenetic mechanism. Methylation occurs on lysine and arginine residues at multiple sites on histones and the tight regulation of the histone methylation status is absolutely required for normal cell physiology and safeguards against aberrant cell growth. Thus, enzymes affecting histone methylation play seminal roles in cellular homeostasis and, accordingly, dysregulation of both histone methyltransferases as well as the opposing demethylases is thought to be capable of inducing cancer (5,6). However, the roles of the enzymes determining histone methylation in colorectal tumors are largely unexplored.The family of human Jumonji C domain containing proteins comprises 30 members, many of which have been shown to function as histone demethylases (7). These include the four related lysine-specific demethylase 4 (KDM4) proteins...

show abstract

“…20,21 Furthermore, JMJD2B levels are de-regulated in a number of human cancers, suggesting that this is an important protein. 22 Given our findings that PITX1 impacts on HIF- Figure 1.…”

Section: Pitx1 Depletion Results In Differential Regulation Of Hif-1amentioning

confidence: 99%

PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

et al. 2014

View full text Add to dashboard Cite

show abstract

HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism

Cited by 79 publications

References 31 publications

JMJD2B Promotes Epithelial–Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis

JMJD2B Promotes Epithelial–Mesenchymal Transition by Cooperating with β-Catenin and Enhances Gastric Cancer Metastasis

Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase

PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

Contact Info

Product

Resources

About