Highlights d Oncogenic BRD4-S and tumor-suppressive BRD4-L in breast cancer d Inducible BRD4-L/S transgenic mice exhibiting opposing functions of BRD4 isoforms d Genome-wide RNA-seq, ChIP-seq, and CUT&RUN profiling of BRD4-S and BRD4-L d EN1/BRD4-S-coregulated enhancer modulating the matrisome ECM network
Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator in response to hypoxia and its transcriptional activity is crucial for cancer cell mobility. Here we present evidence for a novel epigenetic mechanism that regulates HIF-1 transcriptional activity and HIF-1-dependent migration of glioblastoma cells. The lysine methyltransferases G9a and GLP directly bound to the α subunit of HIF-1 (HIF-1α) and catalyzed mono- and di-methylation of HIF-1α at lysine (K) 674 in vitro and in vivo. K674 methylation suppressed HIF-1 transcriptional activity and expression of its downstream target genes PTGS1, NDNF, SLC6A3, and Linc01132 in human glioblastoma U251MG cells. Inhibition of HIF-1 by K674 methylation is due to reduced HIF-1α transactivation domain function but not increased HIF-1α protein degradation or impaired binding of HIF-1 to hypoxia response elements. K674 methylation significantly decreased HIF-1-dependent migration of U251MG cells under hypoxia. Importantly, we found that G9a was downregulated by hypoxia in glioblastoma, which was inversely correlated with PTGS1 expression and survival of patients with glioblastoma. Therefore, our findings uncover a hypoxia-induced negative feedback mechanism that maintains high activity of HIF-1 and cell mobility in human glioblastoma.
Arsenic has been shown to inhibit methyl methane-sulphonate (MMS)-induced DNA repair but the exact mechanism remains controversial. The purpose of this investigation is to examine which step of DNA repair is most sensitive to arsenite (As) and how As inhibits it. The results from single-cell alkaline electrophoresis, showing post-treatment with As increased DNA strand breaks in MMS-treated cells, suggest that that the excision step seems to be less sensitive to As than later steps. To test this hypothesis, hydroxyurea (Hu) plus cytosine-beta-D-arabinofuranoside (AraC) were used to block DNA polymerization, allowing the DNA strand breaks to accumulate. These experiments indicated that As had weak inhibitory effects on DNA strand break accumulation. However, As inhibited the rejoining of those DNA strand breaks which could be rejoined within 4 h after release from blockage by Hu plus AraC. To further elucidate this mechanism, a cell extract was used to compare the relative sensitivity of the various steps in DNA repair to As. The potency of the As inhibitory effect as deduced from concentration-response curves were: ligation of poly(rA).oligo(dT) > ligation of poly(dA).oligo(dT) approximately DNA polymerization > or = DNA repair synthesis > excision. As is known to inhibit the activity of pyruvate dehydrogenase by interacting with vicinal dithiol groups. Dithiothreitol could effectively remove As inhibition of both the ligation of poly(rA).oligo(dT) and the activity of pyruvate dehydrogenase but had no obvious effect on As inhibition of poly(dA).oligo(dT) ligation. Since DNA ligase III contains vicinal dithiol groups, we postulate that As may inhibit DNA break rejoining by interacting with the vicinal dithiols to inactivate DNA ligation in MMS-treated cells.
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