Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1␤ and an oxygen-regulated subunit HIF-1␣ (or its paralogs HIF-2␣ and HIF-3␣). The stability and activity of the ␣ subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1␣ trigger its association with pVHL E3 ligase complex, leading to HIF-1␣ degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1␣ subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator responsible for the induction of genes that facilitate adaptation and survival of cells and the whole organism from normoxia (ϳ21% O 2 ) to hypoxia (ϳ1% O 2 ) (Wang et al., 1995;Semenza, 1998). Since the identification of HIF, 2 decades ago, our knowledge of it has grown exponentially. Because of the realization that hypoxia has a strong impact, via gene expression, on cell biology and mammalian physiology, there has been enormous growing interest in the biology of the HIF-1 pathway and its role in human diseases such as cancer. Therefore, this review considers what has been learned about HIF-1: its discovery, its regulation, its target gene, its role in development and disease, and its implication for therapy. The Discovery of HIF-1HIF-1␣. HIF-1 was discovered by the identification of a hypoxia response element (HRE; 5Ј-RCGTG-3Ј) in the 3Ј enhancer of the gene for erythropoietin (EPO), a hormone that stimulates erythrocyte proliferation and undergoes hypoxiainduced transcription (Goldberg et al., 1988;Semenza et al., 1991). Subsequent studies have revealed the protein that binds to the HRE under hypoxic conditions as HIF-1, a heterodimeric complex consisting of a hypoxically inducible subunit HIF-1␣ and a constitutively expressed subunit HIF-1␤ (Wang et al., 1995). HIF-1␤ is also known as the aryl hydrocarbon nuclear translocator (ARNT), which was originally identified as a binding partner of the aryl hydrocarbon receptor (Reyes et al., 1992), whereas HIF-1␣ was newly discovered. These proteins belong to the basic helix-loop-helixPer-ARNT-Sim (bHLH-PAS) protein family ( Fig. 1) (Wang et al., 1995). The bHLH and PAS motifs are required for heterodimer formation between the HIF-1␣ and HIF-1␤ ...

We have previously reported that carcinogenic nickel compounds decreased global histone H4 acetylation and silenced the gpt transgene in G12 Chinese hamster cells. However, the nature of this silencing is still not clear. Here, we report that nickel ion exposure increases global H3K9 mono-and dimethylation, both of which are critical marks for DNA methylation and long-term gene silencing. In contrast to the up-regulation of global H3K9 dimethylation, nickel ions decreased the expression and activity of histone H3K9 specific methyltransferase G9a. Further investigation demonstrated that nickel ions interfered with the removal of histone methylation in vivo and directly decreased the activity of a Fe(II)-2-oxoglutarate-dependent histone H3K9 demethylase in nuclear extract in vitro. These results are the first to show a histone H3K9 demethylase activity dependent on both iron and 2-oxoglutarate. Exposure to nickel ions also increased H3K9 dimethylation at the gpt locus in G12 cells and repressed the expression of the gpt transgene. An extended nickel ion exposure led to increased frequency of the gpt transgene silencing, which was readily reversed by treatment with DNAdemethylating agent 5-aza-2-deoxycytidine. Collectively, our data strongly indicate that nickel ions induce transgene silencing by increasing histone H3K9 dimethylation, and this effect is mediated by the inhibition of H3K9 demethylation.Posttranslational modifications of histone N-terminal tails are important in chromatin organization, gene transcription, and DNA replication and repair (19). To date, a diverse array of histone modifications has been identified, including acetylation, methylation, phosphorylation, and ubiquitination (28). Among them, methylation of histone H3 lysine 9 (H3K9) is one of the best-studied modifications. H3K9 may be mono-, di-, or trimethylated without changing the positive charge of the lysine residue. Trimethylated H3K9 is typically connected with constitutive heterochromatin, while mono-and dimethylated H3K9 are mainly located in euchromatin and generally linked to repressed promoter regions (29). Suv39h family enzymes are responsible for trimethylation of H3K9 in vivo (27,29), while G9a and GLP/EuHMTase 1 are two major histone methyltransferases responsible for H3K9 dimethylation in vivo (35,36). Genetic ablation of either G9a or GLP/EuHMTase 1 dramatically diminished global H3K9 dimethylation in mouse embryonic stem cells (35,36).Methylation of histone lysines had long been thought of as a "permanent" modification since there was no known enzyme to demethylate. However, this dogma was challenged by the recent discoveries of histone H3 lysine 4 (H3K4) demethylase LSD1 and H3 lysine 36 (H3K36) demethylase JHDM1 (JmjC domain-containing histone demethylase 1) (32, 39). Although both LSD1 and JHDM1 can remove the methyl group from lysine residues on histone H3, they utilize different mechanisms to demethylate. LSD1 is a flavin-dependent amine oxidase and removes the methyl group from mono-or dimethyl H3K4 by catalyzing the...

N-myc downstream-regulated gene 1 (NDRG1) is an intracellular protein that is induced under a wide variety of stress and cell growth-regulatory conditions. NDRG1 is up-regulated by cell differentiation signals in various cancer cell lines and suppresses tumor metastasis. Despite its specific role in the molecular cause of Charcot-Marie-Tooth type 4D disease, there has been more interest in the gene as a marker of tumor progression and enhancer of cellular differentiation. Because it is strongly up-regulated under hypoxic conditions, and this condition is prevalent in solid tumors, its regulation is somewhat complex, governed by hypoxia-inducible factor 1 alpha (HIF-1alpha)- and p53-dependent pathways, as well as its namesake, neuroblastoma-derived myelocytomatosis, and probably many other factors, at the transcriptional and translational levels, and through mRNA stability. We survey the data for clues to the NDRG1 gene's mechanism and for indications that the NDRG1 gene may be an efficient diagnostic tool and therapy in many types of cancers.

Arsenic is a metalloid compound that is widely distributed in the environment. Human exposure of this compound has been associated with increased cancer incidence. Although the exact mechanisms remain to be investigated, numerous carcinogenic pathways have been proposed. Potential carcinogenic actions for arsenic include oxidative stress, genotoxic damage, DNA repair inhibition, epigenetic events, and activation of certain signal transduction pathways leading to abberrant gene expression. In this article, we summarize current knowledge on the molecular mechanisms of arsenic carcinogenesis with an emphasis on ROS and signal transduction pathways.