Hypoxia-induced methylation of a pontin chromatin remodeling factor

Abstract

Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Although Pontin is frequently overexpressed in human cancers of various types and implicated in oncogenic functions, the upstream signaling network leading to the regulation of Pontin that in turn affects transcription of downstream target genes has not been extensively studied. Here, we identify Pontin is methylated by G9a/GLP methyltransferases in hypoxic condition and potentiates HIF-1α-mediated activation by increasing the recruitment of p300 coactivator to a subset of HIF-1α target promoters. Intriguingly, Pontin methylation results in the increased invasive and migratory properties by activating downstream target gene, Ets1. In contrast, inhibition of Pontin methylation results in the suppression of tumorigenic and metastatic properties. Together, our data provide new approaches by targeting Pontin methylation and its downstream targets for the development of therapeutic agents for human cancers.epigenetics | transcriptional regulation | covalent nonhistone modification

Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression

“…The histone demethylase jumonji domain (JMJD) containing protein 1A demethylates dimethylated lysine 9 of histone H3 (H3K9me2) and enhances transcription of the HIF-1 target genes SLC2A3 and KDM3A (25). The ATP-dependent chromatin remodeling factors Pontin and Reptin regulate HIF-1 transcriptional activity as well (26,27). Pontin interacts with HIF-1α to enhance transcription of the HIF-1 target gene ETS1, thereby promoting migration of MCF-7 breast cancer cells (26).…”

“…The ATP-dependent chromatin remodeling factors Pontin and Reptin regulate HIF-1 transcriptional activity as well (26,27). Pontin interacts with HIF-1α to enhance transcription of the HIF-1 target gene ETS1, thereby promoting migration of MCF-7 breast cancer cells (26). Methylation of Pontin by the histone methyltransferases G9a and GLP is required for coactivator function.…”

FIH Is an Oxygen Sensor in Ovarian Cancer for G9a/GLP-Driven Epigenetic Regulation of Metastasis-Related Genes

“…A few research groups argued that G9a is upregulated at the post-translational level under hypoxia (23,43), but other groups showed that G9a expression is constant regardless of the O 2 level (44). In fact, we could not observe any change in G9a and GLP expression under moderately and severely hypoxic conditions in all experiments.…”

Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis

“…[13][14][15] HIF-1 plays a pivotal role in adaptive responses to hypoxia by modulating various cellular functions through the induction of target genes. [16][17][18][19] Overexpression of HIF-1 has been found in various cancer types and contributes to cancer progression and resistance to therapy.…”