Hypoxia Induces Genomic DNA Demethylation through the Activation of HIF-1α and Transcriptional Upregulation of MAT2A in Hepatoma Cells

Abstract

Hypoxia-inducible factor 1 (HIF-1) emerges as a crucial player in tumor progression. However, its role in hepatocellular carcinoma (HCC), especially its relation with global DNA methylation patterns in HCC under hypoxic tumor microenvironment is not completely understood. Methionine adenosyltransferase 2A (MAT2A) maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status. In this study, we investigated the link between HIF-1a and MAT2A as a mechanism responsible for the change in genomic DNA methylation patterns in liver cancer under hypoxia conditions. Our results showed that hypoxia induces genomic DNA demethylation in CpG islands by reducing the steady-state SAM level both in vitro and in vivo. In addition, HIF-1a and MAT2A expression is correlated with tumor size and TNM stage of liver cancer tissues. We further showed that hypoxia-induced MAT2A expression is HIF-1a dependent and requires the recruitment of p300 and HDAC1. We also identified an authentic consensus HIF1a binding site in MAT2A promoter by site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Taken together, we show for the first time that hypoxia induces genomic DNA demethylation through the activation of HIF-1a and transcriptional upregulation of MAT2A in hepatoma cells. These findings provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC. Mol Cancer Ther; 10(6); 1113-23. Ó2011 AACR.

Long non-coding RNAs in cancer invasion and metastasis

“…The association between lncRNA-LET and NF90 indirectly regulates the protein levels of HIF-1a and CDC42, and the HIF-1a/HDAC3/lncRNA-LET/NF90 signaling pathway might provide a positive feedback loop that augments the HIF-1a response, leading to hypoxiainduced cancer cell invasion and tumor metastasis (Figure 2). 12 These results indicate that lncRNA-LET acts as a tumor suppressor and may promote HCC metastasis when downregulated, suggesting that it may be an important target for tumor therapy.…”

“…Furthermore, a lower lncRNA-LET level was found to be associated with tumor metastasis and determined to have tumor suppressor activity. 42 Hypoxic microenvironments have a critical role in the metastasis of various cancers, 12,43 and it has been demonstrated that a hypoxic microenvironment suppresses lncRNA-LET through histone deacetylase 3 (HDAC3) activation, resulting in reduced histone H3 and H4 acetylation levels in the lncRNA-LET promoter region. NF90 is a doublestranded RNA-binding protein implicated in the translational control of many target mRNAs, including hypoxia-inducible factor 1 alpha (HIF1a) subunit and cell division cycle 42 (CDC42) 44,45 The lncRNA-LET transcript was found to associate with NF90 to promote NF90 protein ubiquitination and subsequent degradation, and the downregulation of lncRNA-LET was found to be a key step in the stabilization of nuclear factor 90 protein via the ubiquitin-proteasome pathway.…”

“…Then, the cancer cells invade their target tissues to form micrometastases and eventually form a secondary tumor. As metastatic cancers are frequently refractory to the therapeutic treatments that are effective on the primary cancers, 12 it is critical to explore the knowledge of the specific regulatory mechanisms underlying tumor invasion and metastasis. In this review, we summarize the respective biological mechanisms of different lncRNAs related to cancer invasion and/or metastasis ( Table 2).…”

Real-time dynamics of methyl-CpG-binding domain protein 3 and its role in DNA demethylation by fluorescence correlation spectroscopy

“…[42][43][44] In other words, hypoxia is highly related to hypomethylation and may necessarily be active in maintaining low levels of DNA modifications required for stemness or tumorigenesis.…”

Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver

“…Furthermore, it has been shown that hypo-methylation plays a crucial role in the onset of liver fibrosis and the progression of the disease to cancer (Komatsu et al, 2012). Genomic DNA hypo-methylation is also thought to provide a molecular mechanism for the role of hypoxia in hepatocellular carcinoma (Liu et al, 2011). Hypo-methylation has also been reported as a result of exposure to furan and has been linked to tumors induced by this carcinogen (Chen et al, 2012).…”