Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer

Li, Wenjuan; Zhao, Li; Zang, Wen; Liu, Zhifang; Chen, Long; Liu, Tiantian; Xu, Dawei; Jia, Jihui

doi:10.1016/j.bbrc.2011.11.045

Cited by 65 publications

(68 citation statements)

References 26 publications

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“…In our previous study, we identified the functional role of JMJD2B in gastric cancer cell proliferation, survival, and tumorigenesis (24). Interestingly, we noted that knocking down JMJD2B expression by siRNA in HGC27 and MGC803 gastric cancer cells (spindle-shaped malignant gastric epithelial cell lines with high expression of JMJD2B and loosen cell-cell adhesion) not only inhibited cell proliferation, but also induced tight cell-cell contacts and cobblestone-like appearance that represented epithelial morphology (Fig.…”

Section: Jmjd2b Inhibition Induces the Epithelial Morphology Of Gastrmentioning

confidence: 93%

“…It is also reported that JMJD2B/MLL2 complex is copurified with ERa, with H3K9 demethylation, and H3K4 methylation in ERa-activated transcription, which provides a mechanism for the role of JMJD2B in breast carcinogenesis (23). In our previous study, we demonstrated that JMJD2B promoted proliferation and survival of gastric cancer cells (24). However, whether and how JMJD2B is involved in gastric cancer invasion and metastasis arouses our interest.…”

Section: Introductionmentioning

confidence: 95%

“…Total cellular proteins were extracted and Western blot analysis was performed as described (24). Cellular proteins (80 mg) were separated for Western blot analysis.…”

Section: Western Blot Analysis and Coimmunoprecipitationmentioning

confidence: 99%

“…Immunohistochemical analysis was performed as previously described (24). The procedure was described in detail in Supplementary Materials and Methods.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…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%

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

Zhao

Zang

et al. 2013

Clinical Cancer Research

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100

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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.

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Section: Jmjd2b Inhibition Induces the Epithelial Morphology Of Gastrmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 95%

“…Total cellular proteins were extracted and Western blot analysis was performed as described (24). Cellular proteins (80 mg) were separated for Western blot analysis.…”

Section: Western Blot Analysis and Coimmunoprecipitationmentioning

confidence: 99%

“…Immunohistochemical analysis was performed as previously described (24). The procedure was described in detail in Supplementary Materials and Methods.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 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

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100

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Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Mallm

Windisch

Biran

et al. 2019

Intl Journal of Cancer

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Tumor‐initiating cells are a subpopulation of cells that have self‐renewal capacity to regenerate a tumor. Here, we identify stem cell‐like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3–H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

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Targeting the KDM4B–AR–c‐Myc axis promotes sensitivity to androgen receptor‐targeted therapy in advanced prostate cancer

Tang

Dai

et al. 2020

The Journal of Pathology

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The histone demethylase KDM4B functions as a key co‐activator for the androgen receptor (AR) and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 methylation marks. Constitutively active androgen receptor confers anti‐androgen resistance in advanced prostate cancer. However, the role of KDM4B in resistance to next‐generation anti‐androgens and the mechanisms of KDM4B regulation are poorly defined. Here we found that KDM4B is overexpressed in enzalutamide‐resistant prostate cancer cells. Overexpression of KDM4B promoted recruitment of AR to the c‐Myc (MYC) gene enhancer and induced H3K9 demethylation, increasing AR‐dependent transcription of c‐Myc mRNA, which regulates the sensitivity to next‐generation AR‐targeted therapy. Inhibition of KDM4B significantly inhibited prostate tumor cell growth in xenografts, and improved enzalutamide treatments through suppression of c‐Myc. Clinically, KDM4B expression was found upregulated and to correlate with prostate cancer progression and poor prognosis. Our results revealed a novel mechanism of anti‐androgen resistance via histone demethylase alteration which could be targeted through inhibition of KDM4B to reduce AR‐dependent c‐Myc expression and overcome resistance to AR‐targeted therapies. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer

Cited by 65 publications

References 26 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

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Targeting the KDM4B–AR–c‐Myc axis promotes sensitivity to androgen receptor‐targeted therapy in advanced prostate cancer

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