The histone demethylase enzymes KDM3A and KDM4B co-operatively regulate chromatin transactions of the estrogen receptor in breast cancer

Many estrogen receptor (ER)-positive breast cancers develop resistance to endocrine therapy but retain canonical receptor signalling in the presence of selective ER antagonists. Numerous co-regulatory proteins, including enzymes that modulate the chromatin environment, control the transcriptional activity of the ER. Targeting ER co-regulators has therefore been proposed as a novel therapeutic approach. By assessing DNA-binding dynamics in ER-positive breast cancer cells, we have identified that the histone H3 lysine 9 demethylase enzymes, KDM3A and KDM4B, co-operate to regulate ER activity via an auto-regulatory loop that facilitates the recruitment of each co-activating enzyme to chromatin. We also provide evidence that suggests that KDM3A primes chromatin for deposition of the ER pioneer factor FOXA1 and recruitment of the ER-transcriptional complex, all prior to ER recruitment, therefore establishing an important mechanism of chromatin regulation involving histone demethylases and pioneer factors, which controls ER functionality. Importantly, we show via global gene-expression analysis that a KDM3A/KDM4B/FOXA1 co-regulated gene signature is enriched for pro-proliferative and ER-target gene sets, suggesting that abrogation of this network could be an efficacious therapeutic strategy. Finally, we show that depletion of both KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than knockdown of each individual enzyme, suggesting that targeting both enzymes represents a potentially efficacious therapeutic option for ER-driven breast cancer

Ye Ink Stand

Letters from fans in Mythril #

Ye Ink Stand

Letters and comments from contributors and fans in Mythril #

Isospin-1/2 DπD\pi scattering and the lightest D0∗D_0^\ast resonance from lattice QCD

Isospin-1/2 $D\pi$ scattering amplitudes are computed using lattice QCD, working in a single volume of approximately $(3.6\; \mathrm{fm})^3$ and with a light quark mass corresponding to $m_\pi\approx239$ MeV. The spectrum of the elastic $D\pi$ energy region is computed yielding 20 energy levels. Using the L\"uscher finite-volume quantisation condition these energies are translated into constraints on the infinite volume scattering amplitudes. For the first time, we find a complex $D_0^\ast$ resonance pole from lattice QCD, strongly coupled to the $S$-wave $D\pi$ channel, with a mass $m\approx 2200$ MeV and a width $\Gamma\approx400$ MeV. Combined with earlier work investigating the $D_{s0}^\ast$, and $D_0^\ast$ with heavier light quarks, similar couplings between each of these scalar states and their relevant meson-meson scattering channels are determined. The mass of the $D_0^\ast$ is consistently found well below that of the $D_{s0}^\ast$, in contrast to the currently reported experimental result.Comment: 39 pages, 13 figure

Isospin-1/2 Dπ scattering and the lightest D 0 ∗ resonance from lattice QCD

Abstract: Isospin-1/2 Dπ scattering amplitudes are computed using lattice QCD, working in a single volume of approximately (3.6 fm)3 and with a light quark mass corresponding to mπ ≈ 239 MeV. The spectrum of the elastic Dπ energy region is computed yielding 20 energy levels. Using the Lüscher finite-volume quantisation condition, these energies are translated into constraints on the infinite-volume scattering amplitudes and hence enable us to map out the energy dependence of elastic Dπ scattering. By analytically continuing a range of scattering amplitudes, a D0∗ resonance pole is consistently found strongly coupled to the S-wave Dπ channel, with a mass m ≈ 2200 MeV and a width Γ ≈ 400 MeV. Combined with earlier work investigating the Ds0∗, and D0∗ with heavier light quarks, similar couplings between each of these scalar states and their relevant meson-meson scattering channels are determined. The mass of the D0∗ is consistently found well below that of the Ds0∗, in contrast to the currently reported experimental result

SOFIA/FORCAST and Spitzer/IRAC Imaging of the Ultra Compact H II Region W3(OH) and Associated Protostars in W3

We present infrared observations of the ultra-compact H II region W3(OH) made by the FORCAST instrument aboard SOFIA and by Spitzer/IRAC. We contribute new wavelength data to the spectral energy distribution, which constrains the optical depth, grain size distribution, and temperature gradient of the dusty shell surrounding the H II region. We model the dust component as a spherical shell containing an inner cavity with radius ~ 600 AU, irradiated by a central star of type O9 and temperature ~ 31,000 K. The total luminosity of this system is 71,000 L_solar. An observed excess of 2.2 - 4.5 microns emission in the SED can be explained by our viewing a cavity opening or clumpiness in the shell structure whereby radiation from the warm interior of the shell can escape. We claim to detect the nearby water maser source W3 (H2O) at 31.4 and 37.1 microns using beam deconvolution of the FORCAST images. We constrain the flux densities of this object at 19.7 - 37.1 microns. Additionally, we present in situ observations of four young stellar and protostellar objects in the SOFIA field, presumably associated with the W3 molecular cloud. Results from the model SED fitting tool of Robitaille et al. (2006, 2007} suggest that two objects (2MASS J02270352+6152357 and 2MASS J02270824+6152281) are intermediate-luminosity (~ 236 - 432 L_solar) protostars; one object (2MASS J02270887+6152344) is either a high-mass protostar with luminosity 3000 L_solar or a less massive young star with a substantial circumstellar disk but depleted envelope; and one object (2MASS J02270743+6152281) is an intermediate-luminosity (~ 768 L_solar) protostar nearing the end of its envelope accretion phase or a young star surrounded by a circumstellar disk with no appreciable circumstellar envelope.Comment: 12 pages, 8 figures, 2 tables, accepted by Ap