Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G1/S transition
Introduction
Histone methylation plays an important dynamic role in regulating chromatin structure. Precise coordination and organization of chromatin structures are crucial for normal cellular processes such as DNA replication, repair, recombination and transcription. Previously, histone methylation had been considered to be a static modification, but the identification of histone demethylases revealed that this modification is dynamically regulated [1], [2], [3]. So far, two families of histone demethylases have been identified. One is lysine-specific demethylase-1 (LSD1), a flavin-dependent amine oxidase, which specifically demethylates mono- and dimethylated Lys 4 and Lys 9 of histone H3, but has no activity on trimethylated lysines owing to its catalytic requirement for a protonatable methyl ε-ammonium group [1], [4]. The other class of histone demethylases belongs to the JmjC protein hydroxylase family [2]. JmjC histone demethylases are members of the cupin superfamily of α-ketoglutarate (αKG)-dependent Fe(II) oxygenases, which catalyze a diverse array of reactions through an oxo-ferryl(IV) species [5]. The JmjC enzymes demethylate methyllysines through hydroxylation of the ζ-methyl groups, which forms an unstable hemiaminal intermediate that spontaneously decomposes to yield formaldehyde and the demethylated lysine, in addition to the αKG-derived products carbon dioxide and succinate [6]. In spite of a large body of information on the prominent role of histone demethylases in transcriptional regulation, their physiological functions and their involvement in human disease are still not well-investigated.
In order to examine a possible involvement of a demethylase(s) in human carcinogenesis, we examined the expression profiles of proteins containing a JmjC histone demethylase domain in clinical tissues and found that expression levels of Jumonji domain containing 2A (JMJD2A) were significantly up-regulated, compared with their corresponding normal tissues, in various types of human cancer. JMJD2A, also named KDM4A or JHDM3A, is one of the JMJD2 family members, which are trimethyllysine-specific histone demethylases [7], [8], [9], [10], [11]. In human, six JMJD2 homologs have been identified, termed JMJD2A through JMJD2F [12]. Ectopic expression of mammalian JMJD2A, JMJD2B, JMJD2C and JMJD2D diminishes the global levels of H3K9me3 and H3K36me3 [7], [8], [9], [10], [13]. RNA interference targeting JMJD2 in Caenorhabditis elegans was shown to elevate germ-cell apoptosis [10]. Human JMJD2C has been implicated its critical role in the regulation of androgen receptor-responsive genes [14]. However, the pathological role of deregulation of JMJD2 family members in human disease including has not been well investigated.
Here, we demonstrate involvement of JMJD2A in human carcinogenesis and its candidacy as a candidate therapeutic target for various types of cancer.
Section snippets
Bladder tissue samples and RNA preparation
Bladder tissue sampling and RNA preparation were described previously [15]. Briefly, 122 surgical specimens of primary urothelial carcinoma were collected, either at cystectomy or transurethral resection of bladder tumor (TURBT), and snap frozen in liquid nitrogen. Twenty-five specimens of normal bladder urothelial tissue were collected from areas of macroscopically normal bladder urothelium in patients with no evidence of malignancy. Vimentin is primarily expressed in messenchymally derived
Expression levels of JMJD2A are elevated in clinical cancer tissues
We conducted the expression profile analysis of the JmjC histone demethylase genes in a small subset of clinical bladder cancer samples by quantitative real-time PCR and found significant elevation of JMJD2A expression in cancers compared with normal bladder tissues (data not shown). Subsequently, we analyzed 122 bladder cancer samples and 25 normal control samples (British), and confirmed significant elevation of JMJD2A expressions in tumor cells compared with in normal cells (P < 0.0001,
Discussion
Through expression profile and ChIP-Seq analyses, JMJD2A appears to directly regulate some cancer-related genes. ADAM12 (A Disintegrin And Metalloprotease 12) is a multifunctional protein with a metalloprotease domain, disintegrin-like region, cysteine-rich domain, transmembrane domain, a prodomain remaining associated with the mature form of the protein and a cytoplasmic tail that can signal through phosphotidyl inositol-3-kinases (PI3K) and other pathways [30]. ADAM12 is expressed at low
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We thank Professor Gillian Murphy and the members of her laboratory for substantial technical support. We also thank Ms. Yuka Yamane, Mr. Kazuhiro Maejima and Ms. Yukiko Iwai for technical assistance. Our bio-repository is supported by funding NIHR and the Cambridge Biomedical Research Centre. This work was supported by a Grant-in Aid for Young Scientists (A) (22681030) from the Japan Society for the Promotion of Science.
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These authors contributed equally to this work.