Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia

Abstract

Hypoxia is commonly found in human solid cancers and serves as a selective environment for the survival of aggressive cancer cells and as protection from anti-cancer therapies. In addition to a shift to anaerobic metabolism, the cellular response to hypoxia includes cessation of cell division and/or cell death. These mechanisms have still not been defined. Identification of the members of hypoxia-induced growth arrest pathways remain incomplete. We have undertaken an expression microarray analysis of the cellular response to hypoxia in diverse cell lines. An identified cohort of genes is reliably upregulated in various cells in response to hypoxia, as validated by reverse-transcriptase polymerase chain reaction (RT-PCR). One of the upregulated targets corresponds to an expressed sequence tag encoded by JMJD1A (a gene also known as JHDM2A), which has been identified as a histone demethylase that regulates the transcription of androgen receptor targets. We confirm, by RT-PCR, the upregulation of JMJD1A after hypoxia and desferroxamine treatment in multiple cell lines. We also show that JMJD1A is predominantly, but not exclusively, a nuclear protein. Immunofluorescent staining of HeLa cells shows a shift of cytoplasmic JMJD1A into the nucleus on hypoxia treatment. Immunohistochemical staining has revealed that JMJD1A is widely expressed in tissues, even in cells that are not known to express the androgen receptor, and is significantly increased in smooth muscle cells upon hypoxia treatment.

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

“…Many of these histone demethylases have HREs in their promoters and are induced by HIF-1a ). For example, JARID1B (KDM5B), JMJD1A (KDM3A), JMJD2B (KDM4B), and JMJD2C (KDM4C) are known to be direct HIF-1a target genes with robust HIF-1a binding to HREs in their promoters and upregulated expression under hypoxic conditions (Pollard et al, 2008;Sar et al, 2009;Krieg et al, 2010;Guo et al, 2012). Under hypoxia, cells ectopically expressing JARID1B had decreased levels of histone 3 lysine 4 methylation (Xia et al, 2009b).…”

Cancer and Altered Metabolism: Potential Importance of Hypoxia-Inducible Factor and 2-Oxoglutarate-Dependent Dioxygenases

“…KDM3A is overexpressed in renal carcinoma, presumably because it is the product of a HIF-responsive gene (Beyer et al 2008; Pollard et al 2008; Wellmann et al 2008; Sar et al 2009; Xia et al 2009; Krieg et al 2010). Downeregulation of KDM3A impairs cancer cell proliferation and invasiveness (Krieg et al 2010; Yamada et al 2011).…”

The Expression of Histone Demethylase JMJD1A in Renal Cell Carcinoma

“…JMJD1A specifically demethylates mono-and dimethylated H3 'Lys-9' residue(H3K9me1/2), which is an important epigenetic mark associated with transcription repression [10]. In hypoxic environment, the expression of JMJD1A is upregulated, which enhances hypoxic gene expression [11][12]. These researches also indicates that the upregulation of JMJD1A expression is associated with cancer development [6,12].…”