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- Smits, Michiel, et al.
(författare)
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Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:1, s. e16282-
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis is a balanced process controlled by pro- and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro-angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro-angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role.
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- Smits, Michiel, et al.
(författare)
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miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis
- 2010
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 1:8, s. 710-720
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor with dismal prognosis. GBM patients have a median survival of less than 2 years. GBM is characterized by fast cell proliferation, infiltrative migration, and by the induction of angiogenesis. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression.METHODS: Here we determined that miR-101 is down-regulated in GBM, resulting in overexpression of the miR-101 target PcG protein EZH2, a histone methyltransferase affecting gene expression profiles in an epigenetic manner.RESULTS: Inhibition of EZH2 in vitro by pre-miR-101, EZH2 siRNA, or small molecule DZNep, attenuated GBM cell growth, migration/invasion, and GBM-induced endothelial tubule formation. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Inhibition of EZH2 in vivo by systemic DZNep administration in a U87-Fluc-mCherry GBM xenograft mouse imaging model resulted in reduced tumor growth.CONCLUSION: Our results indicate that EZH2 has a versatile function in GBM progression and that its overexpression is at least partly due to decreased miR-101 expression. Inhibition of EZH2 may be a potential therapeutic strategy to target GBM proliferation, migration, and angiogenesis.
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- Burillo, S. G., et al.
(författare)
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Molecular line emission in NGC 1068 imaged with ALMA : I. An AGN-driven outflow in the dense molecular gas
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 567, s. 125-
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We investigate the fueling and the feedback of star formation and nuclear activity in NGC 1068, a nearby (D = 14 Mpc) Seyfert 2 barred galaxy, by analyzing the distribution and kinematics of the molecular gas in the disk. We aim to understand if and how gas accretion can self-regulate.Methods. We have used the Atacama Large Millimeter Array (ALMA) to map the emission of a set of dense molecular gas (n(H2) ' 1056 cm3) tracers (CO(3-2), CO(6-5), HCN(4-3), HCO+(4-3), and CS(7-6)) and their underlying continuum emission in the central r ∼ 2 kpc of NGC 1068 with spatial resolutions ∼0:3000:500 (∼20-35 pc for the assumed distance of D = 14 Mpc). Results. The sensitivity and spatial resolution of ALMA give an unprecedented detailed view of the distribution and kinematics of the dense molecular gas (n(H2) ≈ 1056cm3) in NGC 1068. Molecular line and dust continuum emissions are detected from a r ∼ 200 pc off-centered circumnuclear disk (CND), from the 2.6 kpc-diameter bar region, and from the r ∼ 1:3 kpc starburst (SB) ring. Most of the emission in HCO+, HCN, and CS stems from the CND. Molecular line ratios show dramatic order-of-magnitude changes inside the CND that are correlated with the UV/X-ray illumination by the active galactic nucleus (AGN), betraying ongoing feedback. We used the dust continuum fluxes measured by ALMA together with NIR/MIR data to constrain the properties of the putative torus using CLUMPY models and found a torus radius of 20+6 10 pc. The Fourier decomposition of the gas velocity field indicates that rotation is perturbed by an inward radial flow in the SB ring and the bar region. However, the gas kinematics from r ∼ 50 pc out to r ∼ 400 pc reveal a massive (Mmol ∼ 2:7+0:9 1:2 × 107 M) outflow in all molecular tracers. The tight correlation between the ionized gas outflow, the radio jet, and the occurrence of outward motions in the disk suggests that the outflow is AGN driven. Conclusions. The molecular outflow is likely launched when the ionization cone of the narrow line region sweeps the nuclear disk. The outflow rate estimated in the CND, dM=dt ∼ 63+21 37 M yr1, is an order of magnitude higher than the star formation rate at these radii, confirming that the outflow is AGN driven. The power of the AGN is able to account for the estimated momentum and kinetic luminosity of the outflow. The CND mass load rate of the CND outflow implies a very short gas depletion timescale of ≤1 Myr. The CND gas reservoir is likely replenished on longer timescales by efficient gas inflow from the outer disk. © ESO 2014.
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- Viti, S., et al.
(författare)
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Molecular line emission in NGC 1068 imaged with ALMA II. The chemistry of the dense molecular gas
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570, s. 28-
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We present a detailed analysis of Atacama Large Millimeter/submillimeter Array (ALMA) Bands 7 and 9 data of CO, HCO+, HCN, and CS, augmented with Plateau de Bure Interferometer (PdBI) data of the ~200 pc circumnuclear disc (CND) and the ~1.3 kpc starburst ring (SB ring) of NGC 1068, a nearby (D = 14 Mpc) Seyfert 2 barred galaxy. We aim to determine the physical characteristics of the dense gas present in the CND, and to establish whether the different line intensity ratios we find within the CND, as well as between the CND and the SB ring, are due to excitation effects (gas density and temperature differences) or to a different chemistry.Methods. We estimate the column densities of each species in local thermodynamic equilibrium (LTE). We then compute large one-dimensional, non-LTE radiative transfer grids (using RADEX) by using only the CO transitions first, and then all the available molecules to constrain the densities, temperatures, and column densities within the CND. We finally present a preliminary set of chemical models to determine the origin of the gas.Results. We find that, in general, the gas in the CND is very dense (>105 cm-3) and hot (T> 150 K), with differences especially in the temperature across the CND. The AGN position has the lowest CO/HCO+, CO/HCN, and CO/CS column density ratios. The RADEX analyses seem to indicate that there is chemical differentiation across the CND. We also find differences between the chemistry of the SB ring and some regions of the CND; the SB ring is also much colder and less dense than the CND. Chemical modelling does not succeed in reproducing all the molecular ratios with one model per region, suggesting the presence of multi-gas phase components.Conclusions. The LTE, RADEX, and chemical analyses all indicate that more than one gas-phase component is necessary to uniquely fit all the available molecular ratios within the CND. A higher number of molecular transitions at the ALMA resolution is necessary to determine quantitatively the physical and chemical characteristics of these components.
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