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J Pharmacol Sci 115, 453 – 458 (2011)

Journal of Pharmacological Sciences © The Japanese Pharmacological Society

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Pathophysiological Response to Hypoxia — From the Molecular Mechanisms of Malady to Drug Discovery: Epigenetic Regulation of the Hypoxic Response via Hypoxia-Inducible Factor and Histone Modifying Enzymes
Imari Mimura1,2, Tetsuhiro Tanaka1, Youichiro Wada2,Tatsuhiko Kodama2, and Masaomi Nangaku1,*
1

Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
2

Received August 31, 2010; Accepted October 28, 2010

Abstract. The hypoxia responseregulated primarily by hypoxia-inducible factor (HIF) influences metabolism, cell survival, and angiogenesis to maintain biological homeostasis. In addition to the traditional transcriptional regulation by HIF, recent studies have shown that epigenetic modulation such as histone methylation, acetylation, and DNA methylation could change the regulation of the response to hypoxia. Eukaryotic chromatin isknown to be modified by multiple post-translational histone methylation and demethylation, which result in the chromatin conformation change to adapt to hypoxic stimuli. Interestingly, some of the histone demethylase enzymes, which have the Jumonji domain–containing family, require oxygen to function and are induced by hypoxia in an HIF-1–dependent manner. Recent studies have demonstrated thathistone modifiers play important roles in the hypoxic environment such as that in cancer cells and that they may become new therapeutic targets for cancer patients. It may lead to finding a new therapy for cancer to clarify a new epigenetic mechanism by HIF and histone demethylase such as JMJD1A (KDM3A) under hypoxia. Keywords: hypoxia, hypoxia-inducible factor (HIF), histone demethylase, JMJD1A,epigenetics 1. Introduction Transcriptional responses to hypoxia are mainly mediated by hypoxia-inducible factor (HIF), which is a heterodimer consisting of an α subunit (HIF-α) and a β subunit (HIF-β) (1). HIF-α induction is regulated by an oxygen-dependent mechanism, and three HIF-α subunits (HIF-1α, HIF-2α, HIF-3α) have been identified (2). HIF1α and HIF-2α make a complex with HIF-1β, formingHIF-1 and HIF-2, respectively. HIF-1β is constitutively expressed and also referred to as aryl hydrocarbon receptor nuclear translocator subunits (ARNT). The role of HIF-3α is not clear, but its regulation has been reported to be oxygen-dependent as an HIF-1 target gene and it may modulate hypoxic gene induction (3). Structurally
*Corresponding author. mnangaku-tky@umin.ac.jp Published online inJ-STAGE on March 16, 2011 (in advance) doi: 10.1254/jphs.10R19FM

HIF-3α lacks transcriptional activation domains, and several splice variants of HIF-3α such as mouse inhibitory PAS domain protein (IPAS) and human HIF-3α4 may have an inhibitory effect against other HIFs (4, 5). In normoxia, HIFα is post-translationally degraded by prolyl hydroxylases (PHDs) (6). The proline residues are hydroxylatedby PHDs, which results in binding of vonHippel-Lindau (VHL) protein. VHL protein targets HIF for polyubiquitination and proteasomal degradation through its role in substrate recognition as part of an E3 ubiquitin ligase complex. In addition to the hydroxylation of the proline residues by PHDs, one asparagine residue in the C-terminal transactivation domain is also hydroxylated by an asparaginylhydroxylase (FIH1: factor inhibiting HIF-1). Oxygen promotes hydroxylation by FIH-1, which inhibits recruitment of coactivators CBP/p300 and transactivation. In hypoxia, the α-subunit escapes degradation and forms a heterodimer with the β-subunit, which translocates into the nucleus. HIF regulates hundreds of

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hypoxia responsive genes, which are involved in a...