JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer

Abstract

Histone methylation is a dynamic process that participates in a diverse array of cellular processes and has been found to associate with cancer. Recently, several histone demethylases have been identified that catalyze the removal of methylation from histone H3 lysine residues. Through bioinformatic and biochemical analysis, we identified JARID1B as a H3K4 demethylase. Overexpression of JARID1B resulted in loss of tri-, di-, and monomethyl H3K4 but did not affect other histone lysine methylations. In vitro biochemical experiments demonstrated that JARID1B directly catalyzes the demethylation. The enzymatic activity requires the JmjC domain and uses Fe(II) and ␣-ketoglutarate as cofactors. Furthermore, we found that JARID1B is up-regulated in prostate cancer tissues, compared with benign prostate samples. We also demonstrated that JARID1B associates with androgen receptor and regulates its transcriptional activity. Thus, we identified JARID1B as a demethylase capable of removing three methyl groups from histone H3 lysine 4 and up-regulated in prostate cancer. Histone methylation plays an important role in regulating chromatin dynamics and transcription (1). Methylation can occur on either arginine or lysine residues (2). Each lysine can undergo three distinct stages of methylation, having either one (mono), two (di), or three (tri) methyl groups covalently bonded to the amine group of the lysine side chain, and arginine can be mono-or dimethylated (3). Depending on specific residues, methylation can either activate or repress transcription. In general, lysine methylation at H3K9, H3K27, and H4K20 is associated with transcriptional repression, whereas methylation at H3K4, H3K36, and H3K79 is associated with transcriptional activation. However, recent findings have blurred this generality. For example, methylation at H3K9 can result in transcriptional activation, and methylation at H3K36 can repress transcription (4, 5).Methylation had long been considered a stable modification, but recent studies have proved otherwise (6-16). The first histone demethylase identified is LSD1, which can remove di-and monomethylation from H3K4 by using an amine oxidase reaction (8). Subsequently, a JmjC domain-containing protein was identified to possess histone demethylase activity, and the JmjC domain was shown as a demethylase signature motif (9). This class of enzymes catalyzes the removal of methylation by using a hydroxylation reaction and required iron and ␣-ketoglutarate as cofactors. Based on this demethylase signature motif, several proteins were identified to be histone lysine demethylases (6,7,(10)(11)(12)(13)(14)(15)(16).Prostate cancer is the most common nonskin cancer and the second leading cause of cancer in America. Histone methylation has been suggested to be associated with prostate cancer. For example, it was demonstrated that histone methylations and acetylations can be used to predict the risk of prostate cancer recurrence (17). In addition, EZH2, a H3K27 methyltransferase, is shown to be involved in progression...

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

“…The genes JARID1B and KDM4A were described before as highly expressed in PrCa, and function as coactivators of AR (Shin and Janknecht, 2007;Xiang et al, 2007). In contrast, PHF8 mRNA was not previously described as significantly (Po0.0001) overexpressed in PrCa versus normal prostate.…”

“…Eight KDMs are highly expressed in PrCa's (Metzger et al, 2005;Kahl et al, 2006;Wissmann et al, 2007). Various HDACs and KDMs were shown to regulate androgen receptor (AR)-mediated transcription, thus affecting gene expression patterns essential for PrCa proliferation, development and progression (Yamane et al, 2006;Wissmann et al, 2007;Wolf et al, 2007;Xiang et al, 2007;Welsbie et al, 2009). Despite the emerging role of epigenetic processes and large scale mapping of cancer-associated chromatin modifications in PrCa, the functional significance of key 'readers', 'writers' and 'erasers' has not been systematically evaluated.…”

Epigenetic regulation of cancer growth by histone demethylases

“…Although significant expression of PLU-1 is restricted to testis and only low levels of PLU-1 are seen in other normal adult tissues, its expression increases markedly in pathological conditions such as malignant breast cancer, metastatic prostate cancer and testis cancer (Table 1). 27,28 Based on its overexpression in cancer, PLU-1 was suggested as a testis cancer antigen. Yamane et al have shown the oncogenic potential of PLU-1 at the cellular level.…”

Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans

“…However, the mutants showed decreased demethylase activity for both H3K9me2 and H3K27me2 in vivo when their effect was examined in insect cells ( Figure 5B). We also made attempts to deplete H3K4me3 by its demethylase Jarid1b [30], at the same time as or prior to infection by ceKDM7A-expressing virus, but we were unable to quantify the results when the cells were infected simultaneously or sequentially. Nevertheless, our results indicate that the PHD domain-mediated H3K4me3 binding is required for the demethylase activity of ceKDM7A in vivo.…”