Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/b-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear b-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of b-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/b-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and b-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/b-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor. Cancer Res; 71(11); 4028-39. Ó2011 AACR.

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Analysis of new high-resolution seismic-reflection profiles, chirp profiles and previously published sidescan data, together with piston cores on the Danube Fan provide new insight into the recent sedimentation processes in the deep northwestern Black Sea. The latest channel-levee system on the Danube Fan developed probably during the Neoeuxinian lowstand (oxygene isotope stage 2) in a semi-freshwater basin with a water level about 100 m lower than today. Sediment supplied by the Danube was transported to the deep basin through the Viteaz Canyon, which was directly connected to the leveed channel of this system on the middle slope. Channel avulsion was common in the middle fan, as indicated by four main phases of bifurcation. Each phase developed after the same pattern: breaching of the lower and narrower left levee by turbidity currents, building of a unit of High Amplitude Reflection Packets (HARP) by the unchannelized flow while the former channel was abandoned, followed by initiation of a new meandering leveed channel. The northward migration through successive bifurcations is influenced by the asymmetry between levees, hence by the Coriolis effect. In the lower fan where the levees became too low to maintain a stable pathway for the turbiditic flows, channel migration occurred. Locations of HARPs and channels after bifurcation are controlled by the pre-existing bathymetry. Sedimentary deposits are confined between the high levees of unit 0 (the initial phase of the youngest channel-levee system) to the south, and the steep relief of the Dniepr Fan to the north. The HARPs of the most recent phase of avulsion are the most severely constrained by local topography and form a very narrow elongate structure that is at most half as thick as the previous HARPs. Their distal part is not covered by channel-levee systems and is visible both on sidescan mosaics and on chirp profiles and was sampled in core BLKS 98-20. Sea level controlled fan activity but the evolution of the last channel-levee system with several bifurcations during a single sea level lowstand suggests that the primary control of channel avulsion and sand delivery is probably autocyclic. The presence of important HARP sand bodies in the mud-rich Danube Fan is presumed by analogy with a similar seismic facies on the Amazon Fan and indicated by the sands cored in BLKS98-20. However, only drilling of the HARP units could verify this interpretation.

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Emerging studies suggest that low-pass genome sequencing (GS) provides additional diagnostic yield of clinically significant copy-number variants (CNVs) compared with chromosomal microarray analysis (CMA). However, a prospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of low-pass GS compared with CMA is warranted. Methods: A total of 1,023 women undergoing prenatal diagnosis were enrolled. Each sample was subjected to low-pass GS and CMA for CNV analysis in parallel. CNVs were classified according to guidelines of the American College of Medical Genetics and Genomics. Results: Low-pass GS not only identified all 124 numerical disorders or pathogenic or likely pathogenic (P/LP) CNVs detected by CMA in 121 cases (11.8%, 121/1,023), but also defined 17 additional and clinically relevant P/LP CNVs in 17 cases (1.7%, 17/1,023). In addition, low-pass GS significantly reduced the technical repeat rate from 4.6% (47/1,023) for CMA to 0.5% (5/1,023) and required less DNA (50 ng) as input. Conclusion: In the context of prenatal diagnosis, low-pass GS identified additional and clinically significant information with enhanced resolution and increased sensitivity of detecting mosaicism as compared with the CMA platform used. This study provides strong evidence for applying low-pass GS as an alternative prenatal diagnostic test.

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