Advances in histone demethylase KDM4 as cancer therapeutic targets

Lee, Dong Hoon; Kim, Go Woon; Jeon, Yu Hyun; Yoo, Jung; Lee, Sang Wu; Kwon, So Hee

doi:10.1096/fj.201902584r

Cited by 94 publications

(84 citation statements)

References 203 publications

(486 reference statements)

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“…Histone demethylation involves modification of chromatin formation and is a crucial component in the construction of protein complexes controlling gene expression. Histone demethylation enzymes have been proved to be frequently involved in tumor development 12 . Previous study has reported that KDM4A could promote malignant proliferation of human liver cancer cell line Hep3B, which was consistent with our findings 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Among genes which both had a strong binding signal of RFX5 in the promoter region and were closely correlated with RFX5 in RNA expression level ( Fig. 2A), KDM4A had engrossed our attention due to its reported role in several cancers 12 , including HCC 13 . Hence, we decided to focus on the regulation of RFX5 on KDM4A expression in HCC cells.…”

Section: Rfx5 Binds the Promoter Region Of Kdm4a In Hcc Through Analmentioning

confidence: 98%

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RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A

Chen

Xie

Zhao

et al. 2020

Sci Rep

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Regulatory factor X-5 (RFX5) represents a key transcription regulator of MHCII gene expression in the immune system. This study aims to explore the molecular mechanisms and biological significance of RFX5. Firstly, by analyzing ENCODE chromatin immunoprecipitation (ChIP)-seq in HepG2 and TCGA RNA-seq data, we discovered lysine-specific demethylase 4A (KDM4A), also named JMJD2A, to be a major downstream target gene of RFX5. Moreover, RFX5 was verified to bind directly to the KDM4A's promoter region and sequentially promoted its transcription determined by the ChIP-PCR assay and luciferase assay. In addition, RFX5-dependent regulation of KDM4A was demonstrated in HCC. Compared with adjacent non-tumor tissues, the expression levels of KDM4A were significantly raised in HCC tumor tissues. Notably, elevated levels of KDM4A were strongly correlated with HCC patient prognosis. Functionally, KDM4A overexpression largely rescued the growth inhibitory effects of RFX5 deletion, highlighting KDM4A as a downstream effector of RFX5. Mechanistically, the RFX5-KDM4A pathway promoted the progression of the cell cycle from G0/G1 to S phase and was protective against cell apoptosis through regulation of p53 and its downstream genes in HCC. In conclusion, RFX5 could promote HCC progression via transcriptionally activating KDM4A expression. Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed and the second most lethal neoplasm in men worldwide. In 2018 alone, it was identified in an estimated 841,080 newly diagnosed HCC patients and 781,631 HCC-related cancer deaths 1. Although target therapy with sorafenib, lenvatinib, regorafenib and anti-PD1 antibody have achieved better treatment response in certain HCC patients, HCC in its advanced stages is highly lethal in a large proportion of patients 2. Therefore, treatment strategies for HCC are in dire need for more effective molecular therapeutic targets. One of the typical molecular mechanisms of cancer is the accumulation of genetic and epigenetic alterations which eventually disrupts cellular pathways, culminated in uncontrolled cellular growth 3. Intriguingly, a study demonstrated that more than half of its cohort were found to have amplified levels of the 1q21-44 loci on chromosomes, suggesting that this genetic location may house a number of major oncogenes that act as drivers of HCC development, such as CHD1L (1q21.1) 4 , PYCR2 (1q42.12) 5 and BCL9 (1q21.2) 6. Furthermore, analysis of genomics data derived from the TCGA Liver hepatocellular carcinoma (LIHC) revealed regulatory factor X-5 (RFX5), located in the chromosome 1q21 loci, have aberrantly raised expressions in HCC patients 7. A functional study demonstrated that HCC cell colony formation and subcutaneous tumor growth were dependent on RFX5

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Section: Discussionmentioning

confidence: 99%

Section: Rfx5 Binds the Promoter Region Of Kdm4a In Hcc Through Analmentioning

confidence: 98%

RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A

Chen

Xie

Zhao

et al. 2020

Sci Rep

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“…KDM4 proteins, like Gis1, are responsive to nutritional and metabolic signals, in part due to their requirement for α-ketoglutarate (AKG), Fe 2+ , and O 2 for activity [17][18][19][20][21]. KDM4 proteins play important roles in diverse biological processes, and their altered expression or function has been implicated in multiple cancers, cardiovascular diseases, and mental retardation [8,15,[85][86][87][88].…”

Section: Discussionmentioning

confidence: 99%

Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins

Konduri

Wang

Salamat

et al. 2020

Cells

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The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.

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“…For some enzymes, for example, TET2 and the KDM4 sub-family, their role is relatively clear-cut. KDM4A-D are over-expressed in a wide variety of tumour types, and are therefore suggested to play a pro-tumourigenic role in cancer (reviewed in [109]). In contrast, TET2 is thought to be a tumour suppressor, and is either mutated or dysregulated in multiple cancers, particularly haematological malignancies.…”

Section: Og-oxygenases: Disease Mediatorsmentioning

confidence: 99%

“…Therapeutic KDM4 inhibitors are also of interest, given the proposed role for the KDM4 sub-family in promoting tumour growth. However, the development of potent and selective inhibitors has been challenging [109]. Stringent specificity for such inhibitors is paramount, particularly as 2OG-oxygenases have wide-ranging cellular roles.…”

Section: Inhibitionmentioning

confidence: 99%

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators

Fletcher

Coleman

2020

Biochemical Society Transactions

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Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are a conserved enzyme class that catalyse diverse oxidative reactions across nature. In humans, these enzymes hydroxylate a broad range of biological substrates including DNA, RNA, proteins and some metabolic intermediates. Correspondingly, members of the 2OG-dependent oxygenase superfamily have been linked to fundamental biological processes, and found dysregulated in numerous human diseases. Such findings have stimulated efforts to understand both the biochemical activities and cellular functions of these enzymes, as many have been poorly studied. In this review, we focus on human 2OG-dependent oxygenases catalysing the hydroxylation of protein and polynucleotide substrates. We discuss their modulation by changes in the cellular microenvironment, particularly with respect to oxygen, iron, 2OG and the effects of oncometabolites. We also describe emerging evidence that these enzymes are responsive to cellular stresses including hypoxia and DNA damage. Moreover, we examine how dysregulation of 2OG-dependent oxygenases is associated with human disease, and the apparent paradoxical role for some of these enzymes during cancer development. Finally, we discuss some of the challenges associated with assigning biochemical activities and cellular functions to 2OG-dependent oxygenases.

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Advances in histone demethylase KDM4 as cancer therapeutic targets

Cited by 94 publications

References 203 publications

RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A

RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A

Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators

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