**2.2.2.3 Histone demethylase**

It used to be considered that histone methylation was a permanent and irreversible histone modification. However, in recent decade, many enzymes have been identified with the ability to demethylate methylated histone lysine/arginine residues via amine oxidation, hydroxylation or deimination (Cloos et al., 2008). The histone demethylases could be divided into three distinct classes. The rst class (petidylarginine deiminase 4, PADI4) converts a methyl-lysine to citrulline. The second class (lysine-specic demethylase 1, LSD1) reverses histone H3K4 and H3K9 modications by an oxidative demethylation reaction. The third class of demethylases is the family of Jumonji C (JmjC)-domain containing histone demethylases (JHDMs). Contrast to LSD1, JHDMs can demethylate all three methylated states (mono- di- and tri-methylated lysine). Up to now, JHDMs have been found to demethylate H3K36 (JHDM1), H3K9 (JHDM2A) and H3K9/K27 (JHDM3 and JMJD2A-D) (Klose et al., 2006; Miremadi et al., 2007).

Histone demethylase JARID1B (PLU-1) is shown to be overexpressed in breast cancers but low expressed in normal adult tissues, and it is essential for the proliferation of the MCF-7 breast cancer cell line and for the tumor growth of mammary carcinoma cells in nude mice. Several target genes of JARID1B have also been identified to be associated with breast cancer proliferation, such as 14–3–3σ, BRCA1, CAV1, and HOXA5 (Lu et al., 1999; Yamane

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reestablish ER expression in ER- cell lines. But the HDAC inhibitor could potentiate and restore the efficacy of anti-estrogen therapy in preclinical models in either ER+ or ER- breast cancer cells. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy (Thomas et al., 2009). LAQ824 is a novel inhibitor of HDAC that shows antineoplastic activity and can activate genes that produce cell cycle arrest. Combination of the LAQ824 and a DNMT inhibitor (decitabine) showed a synergistic (re-)activation of silenced tumor-suppressor genes in human MDA-MB-231 and MCF-7

Class In vivo preclinical activity Clinical

PA Leukemia, glioblastoma I/II

PB Prostate, endometrial I/II

VA Brain, melanoma I/II

AN-9 NSCLC, leukemia I/II

SAHA Lung, prostate, melanoma I/II

Pyroxamide I

NVP-LAQ824 Colon, multiple myeloma I

Suberic bishydroxamic acid Melanoma, sarcoma

TSA Cervical, hepatoma,

Oxamflatin Melanoma

Neuroblastoma

phase

breast carcinoma cells (Hurtubise et al., 2006).

Carboxylates

(short-chain fatty acids)

Hydroxamic acids

m-Carboxycinnamic acid bishydroxamic acid

Electrophillic ketones

(epoxides)

TPX

AOE

et al., 2007). LSD1 might be a coactivator in the ER signalling (Garcia-Bassets et al., 2007). JMJD1C expression is decreased in breast cancer tissues compared with normal breast tissues, indicating that it might be a tumor suppressor (Wolf et al., 2007).
