The Prognostic Significance of Histone Lysine Demethylase JMJD3/KDM6B in Colorectal Cancer

Tokunaga, Ryuma; Sakamoto, Yasuo; Nakagawa, Shigeki; Miyake, Keisuke; Izumi, Daisuke; Kosumi, Keisuke; Taki, Katsunobu; Higashi, Taishi; Imamura, Yu; Ishimoto, Takatsugu; Iwatsuki, Masaaki; Baba, Yoshifumi; Miyamoto, Yuji; Yoshida, Naoya; Oki, Eiji; Watanabe, Masayuki; Baba, Hideo

doi:10.1245/s10434-015-4879-3

Cited by 42 publications

(41 citation statements)

References 34 publications

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“…JmjC domain-containing proteins function as important regulators of pluripotency and control differentiation of embryonic stem cells (19)(20)(21)(22). Several Jumonji proteins have been either implicated in the regulation of cancer progression or were suggested as a biomarker for several cancer types, like JMJD1A for gastric or JMJD3 for colorectal cancer (23,24).…”

mentioning

confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

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

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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.

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confidence: 99%

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Glaser

Heumüller

Tombor

et al. 2020

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

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“…This gene is essential for life after birth, as knockout mice are born smaller and die perinatally due to respiratory failure (21,61,62). Previous studies have pointed to a potential tumor-suppressive role of KDM6B in specific tissues (such as lung, colon, and pancreas) (30)(31)(32)63), while in others (such as blood, breast, and brain) it may play an opposite tumor-promoting function (24)(25)(26). This demethylase is an important player at the intersection between cellular senescence and cancer (22,29), and it also positively regulates epidermal differentiation (33).…”

Section: Discussionmentioning

confidence: 99%

“…The sphere-forming capability of various SCC cell lines in cell-cycle control, senescence, and differentiation, and may play a role in cancer development in a context-dependent manner (21)(22)(23). In fact, KDM6B expression is upregulated in several malignancies, such as Hodgkin's lymphoma (24), breast cancer (25), gliomas (26), melanoma (27), and renal cell carcinoma (28), while it is suppressed in others, including lung adenocarcinoma and squamous cell carcinoma (29), colon cancer (30,31), and liver and pancreatic cancers (32). While inactivating KDM6B gene mutations are only found in 1%-3% of SCCs (cBioPortal for Cancer Genomics; http:// www.cbioportal.org), the gene, like NOTCH1, has been implicated as a positive determinant of squamous cell differentiation (33).…”

Section: Introductionmentioning

confidence: 99%

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

Labban¹,

Jo²,

Ostano³

et al. 2018

Journal of Clinical Investigation

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“…PHF8 has been reported to be involved in several types of cancer, including breast cancer ( 7 ), non-small cell lung cancer (NSCLC) ( 8 ), acute promyelocytic leukemia ( 9 ) and esophageal squamous cell carcinoma ( 10 ). Previous studies have demonstrated that aberrant epigenetic alteration of histone lysine demethylation is crucial in the development of CRC ( 11 ). PHF2 and Jumonji-domain containing 3 (JMJD3) histone demethylase, a tumor suppressor, are downregulated in colon cancer ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase PHF8 accelerates the progression of colorectal cancer and can be regulated by miR-488 in vitro

Shi

Han

et al. 2017

Molecular Medicine Reports

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Plant homeo domain finger protein 8 (PHF8), as an oncogene, has been highlighted in cancer development and progression. However, its clinical significance and underlying molecular mechanisms in colorectal cancer (CRC) remain to be fully elucidated. In the present study, the role of PHF8 in the progression of CRC was investigated. The mRNA and protein levels of PHF8 in tissues from patients with CRC and cell lines were detected using the reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Cell viability was analyzed using an MTT assay. The targeted genes were predicted using a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell migration was evaluated using a Transwell assay. The results demonstrated that the expression of PHF8 was significantly increased in tumor tissues from patients with CRC and was correlated with tumor-node-metastasis stage. In addition, it was found that overexpressed PHF8 was a predictor of poor overall survival rates in patients with CRC. PHF8 loss-of-function significantly inhibited proliferation and migration, and promoted apoptosis of CRC cells. In addition, bioinformatics methods demonstrated that PHF8 was a putative target of microRNA (miR)-488, and miR-488 was able to inhibit the expression of PHF8 in CRC cells. miR-488 loss-of-function showed increased proliferation and migration, and these effects were reversed by sh-PHF8 transfection in CRC cells. In vitro and in vivo experiments revealed that PHF8 accelerated cancer cell growth and migration, confirming the oncogenic role of PHF8 in human CRC. In conclusion, PHF8 and miR-488 may serve as CRC biomarkers for the prediction of clinical outcome and provide a target for the diagnosis and therapy of CRC.

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The Prognostic Significance of Histone Lysine Demethylase JMJD3/KDM6B in Colorectal Cancer

Abstract: JMJD3 has prognostic significance in CRC and mediates p15INK4B expression. These results imply that elucidation of the JMJD3 role may lead to a new therapeutic approach for CRC patients.

Cited by 42 publications

References 34 publications

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

Histone demethylase PHF8 accelerates the progression of colorectal cancer and can be regulated by miR-488 in vitro

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