一周快讯：本周表观文献精选（2018.3.5）

Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype

Ulrich A. Hirt, Irene C. Waizenegger, Norbert Schweifer, Christian Haslinger, Daniel Gerlach , Jürgen Braunger, Ulrike Weyer-Czernilofsky, Heinz Stadtmüller, Ioannis Sapountzis, Gerd Bader, Andreas Zoephel, Bojan Bister, Anke Baum, Jens Quant, Norbert Kraut, Pilar Garin-Chesa& Günther R. Adolf

原文链接：

http://www.nature.com/articles/s41389-018-0032-z

原文摘要：

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as a target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, a novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation in PC-3 prostate carcinoma cells with an IC50of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC50of 3 nmol/L, whereas cells grown in conventional surface culture are 1000-fold less sensitive. In mice, the compound shows long half-life, high volume of distribution and high oral bioavailability; oral dosing of immunodeficient mice bearing subcutaneous PC-3 prostate adenocarcinoma xenografts resulted in rapid, long-lasting repression of FAK autophosphorylation in tumor tissue. Daily oral administration of BI 853520 to nude mice at doses of 50 mg/kg was well tolerated for prolonged periods of time. In a diverse panel of 16 subcutaneous adenocarcinoma xenograft models in nude mice, drug treatment resulted in a broad spectrum of outcomes, ranging from group median tumor growth inhibition values >100% and tumor regression in subsets of animals to complete lack of sensitivity. Biomarker analysis indicated that high sensitivity is linked to a mesenchymal tumor phenotype, initially defined by loss of E-cadherin expression and subsequently substantiated by gene set enrichment analysis. Further, we obtained microRNA expression profiles for 13 models and observed that hsa-miR-200c-3p expression is strongly correlated with efficacy (R2= 0.889). BI 853520 is undergoing evaluation in early clinical trials.

Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS

Takuji Yamauchi，Takeshi Masuda，Matthew C. Canver，Michael Seiler，Yuichiro Semba，Mohammad Shboul，Mohammed Al-Raqad，Manami Maeda，Vivien A.C. Schoonenberg，Mitchel A. Cole，Claudio Macias-Trevino，Yuichi Ishikawa，Qiuming Yao，Michitaka Nakano，Fumio Arai，Stuart H. Orkin，Bruno Reversade，Silvia Buonamici，Luca Pinello，Koichi Akashi，Daniel E. Bauer，Takahiro Maeda

原文链接：

http://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30012-6

原文摘要：

To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPSloss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPSis dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.

Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms

Brandon L. Pierce  , Lin Tong, Maria Argos, Kathryn Demanelis, Farzana Jasmine, Muhammad Rakibuz-Zaman, Golam Sarwar, Md. Tariqul Islam, Hasan Shahriar, Tariqul Islam, Mahfuzar Rahman, Md. Yunus Muhammad G. Kibriya, Lin S. Chen& Habibul Ahsan

原文链接：

http://www.nature.com/articles/s41467-018-03209-9

原文摘要：Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL-meQTL pairs likely to share a causal variant. We use partial correlation and mediation analyses to identify >400 of these pairs showing evidence of a causal relationship between expression and methylation (i.e., shared mechanism) with many additional pairs we are underpowered to detect. These co-localized pairs are enriched for SNPs showing opposite associations with expression and methylation, although many SNPs affect multiple CpGs in opposite directions. This work demonstrates the pervasiveness of co-regulated expression and methylation in the human genome. Applying this approach to other types of molecular QTLs can enhance our understanding of regulatory mechanisms.

Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation

Huilin Huang, Hengyou Weng, Wenju Sun, Xi Qin, Hailing Shi, Huizhe Wu, Boxuan Simen Zhao, Ana Mesquita1, Chang Liu, Celvie L. Yuan, Yueh-Chiang Hu,Stefan Hüttelmaier, Jennifer R. Skibbe, Rui Su, Xiaolan Deng, Lei Dong, Miao Sun, Chenying Li, Sigrid Nachtergaele, Yungui Wang, Chao Hu, Kyle Ferchen, Kenneth D. Greis, Xi Jiang, Minjie Wei, Lianghu Qu, Jun-Lin Guan, Chuan He, Jianhua Yang & Jianjun Chen

原文链接：

http://www.nature.com/articles/s41556-018-0045-z

原文摘要：N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here, we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTH domain-containing family protein 2, IGF2BPs promote the stability and storage of their target mRNAs (for example, MYC) in an m6A-dependent manner under normal and stress conditions and therefore affect gene expression output. Moreover, the K homology domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Thus, our work reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.