Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as ARID1A, KDM6, and BAP1 are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.

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The molecular mechanisms of endothelial differentiation into a functional vascular network are incompletely understood. To identify novel factors in endothelial development, we used a microarray screen with differentiating embryonic stem (ES) cells that identified the gene for ankyrin repeat and SOCS box protein 4 (ASB4) as the most highly differentially expressed gene in the vascular lineage during early differentiation. Like other SOCS box-containing proteins, ASB4 is the substrate recognition molecule of an elongin B/elongin C/cullin/ Roc ubiquitin ligase complex that mediates the ubiquitination and degradation of substrate protein(s). High levels of ASB4 expression in the embryonic vasculature coincide with drastic increases in oxygen tension as placental blood flow is initiated. However, as vessels mature and oxygen levels stabilize, ASB4 expression is quickly downregulated, suggesting that ASB4 may function to modulate an endothelium-specific response to increasing oxygen tension. Consistent with the hypothesis that ASB4 function is regulated by oxygen concentration, ASB4 interacts with the factor inhibiting HIF1␣ (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mechanism. Additionally, overexpression of ASB4 in ES cells promotes differentiation into the vascular lineage in an oxygen-dependent manner. We postulate that hydroxylation of ASB4 in normoxia promotes binding to and degradation of substrate protein(s) to modulate vascular differentiation.Members of the suppressor of cytokine signaling (SOCS) superfamily are E3 ubiquitin ligase components that contain a C-terminal SOCS box and an N-terminal protein-protein binding domain (21,22). The SOCS box mediates interactions with an elongin B/elongin C/cullin 5/Roc protein complex to constitute a functional E3 ubiquitin ligase complex (19), while the N-terminal protein-protein binding domains recruit substrate proteins to mediate substrate polyubiquitination and proteasome-mediated degradation. In this way, SOCS proteins confer substrate specificity on the E3 ubiquitin ligase complex and are thus tightly regulated at both the transcriptional and posttranslational levels in order to carefully control the steady-state levels of substrate proteins.Ankyrin repeat (AR) and SOCS box proteins (ASBs) constitute one subclass of the SOCS superfamily and are characterized by variable numbers of N-terminal ARs as substratebinding domains (reviewed in reference 13). To date, at least 18 family members have been identified in mammals and preliminary functional characterization is currently under way. So far, ASB proteins have been suggested to mediate the ubiquitination of a broad range of target proteins, including tumor necrosis factor receptor II (ASB3) (2), creatine kinase B (ASB9) (5), and adaptor protein with PH and SH2 domains (APS, ASB6) (47). Since ARs function as generic scaffolds for the creation of modular binding sites that mediate interactions with an almost unlimited variety of binding motifs and domains (33, 43), it is not su...

SUMMARY Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle- invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

Abstract-The formation of new blood vessels in the adult organism not only contributes to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. In this review, we describe the current understanding of where endothelial differentiation from pluripotent progenitor cells occurs during development, how this process is controlled at the molecular level, and what model systems can be used to investigate the earliest steps of blood vessel formation.