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Dive into the research topics where Xiaoxing Wang is active.

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Featured researches published by Xiaoxing Wang.


Cell | 2014

KRAS and YAP1 converge to regulate EMT and tumor survival

Diane D. Shao; Wen Xue; Elsa Beyer Krall; Arjun Bhutkar; Federica Piccioni; Xiaoxing Wang; Anna C. Schinzel; Sabina Sood; Joseph Rosenbluh; Jong W. Kim; Yaara Zwang; Thomas M. Roberts; David E. Root; Tyler Jacks; William C. Hahn

Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling.


Cell | 2013

HIF1A Employs CDK8-Mediator to Stimulate RNAPII Elongation in Response to Hypoxia

Matthew D. Galbraith; Mary A. Allen; Claire L. Bensard; Xiaoxing Wang; Marie K. Schwinn; Bo Qin; Henry W. Long; Danette L. Daniels; William C. Hahn; Robin D. Dowell; Joaquín M. Espinosa

The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.


Cancer Discovery | 2011

Amplification of CRKL Induces Transformation and Epidermal Growth Factor Receptor Inhibitor Resistance in Human Non–Small Cell Lung Cancers

Hihu Wing Cheung; Jinyan Du; Jesse S. Boehm; Frank He; Barbara A. Weir; Xiaoxing Wang; Mohit Butaney; Lecia V. Sequist; Biao Luo; Jeffrey A. Engelman; David E. Root; Matthew Meyerson; Todd R. Golub; Pasi A. Jänne; William C. Hahn

UNLABELLED We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy. SIGNIFICANCE These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs.


Trends in Pharmacological Sciences | 2014

Genomic insights into WNT/β-catenin signaling

Joseph Rosenbluh; Xiaoxing Wang; William C. Hahn

The canonical WNT pathway regulates the stability of the proto-oncogene β-catenin and is aberrantly activated in many cancer types. Studies in a wide range of experimental models confirm that β-catenin activity is required for tumor initiation in cancers where this pathway is deregulated. However, to date this pathway has proven to be challenging to target therapeutically. Moreover, several lines of evidence suggest that other components and regulators of β-catenin exist. Here we will describe recent structural and functional studies describing genomic alterations and new regulators of β-catenin that lead to aberrant activation of the WNT/β-catenin pathway. These findings provide new insights into the biology of WNT/β-catenin signaling and suggest potential therapeutic opportunities.


Nature Communications | 2017

Complementary information derived from CRISPR Cas9 mediated gene deletion and suppression

Joseph Rosenbluh; Han Xu; William F. Harrington; Stanley Gill; Xiaoxing Wang; Francisca Vazquez; David E. Root; Aviad Tsherniak; William C. Hahn

CRISPR-Cas9 provides the means to perform genome editing and facilitates loss-of-function screens. However, we and others demonstrated that expression of the Cas9 endonuclease induces a gene-independent response that correlates with the number of target sequences in the genome. An alternative approach to suppressing gene expression is to block transcription using a catalytically inactive Cas9 (dCas9). Here we directly compare genome editing by CRISPR-Cas9 (cutting, CRISPRc) and gene suppression using KRAB-dCas9 (CRISPRi) in loss-of-function screens to identify cell essential genes. CRISPRc identified 98% of previously defined cell essential genes. After optimizing library construction by analysing transcriptional start sites (TSS), CRISRPi identified 92% of core cell essential genes and did not show a bias to regions involved in copy number alterations. However, bidirectional promoters scored as false positives in CRISRPi. We conclude that CRISPRc and CRISPRi have different off-target effects and combining these approaches provides complementary information in loss-of-function genetic screens.


Cell | 2013

Erratum: β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis (Cell (2012) 151 (1457-1473))

Joseph Rosenbluh; Deepak Nijhawan; Andrew G. Cox; Xingnan Li; James T. Neal; Eric J. Schafer; Travis I. Zack; Xiaoxing Wang; Aviad Tsherniak; Anna C. Schinzel; Diane D. Shao; Steven E. Schumacher; Barbara A. Weir; Francisca Vazquez; Glenn S. Cowley; David E. Root; Jill P. Mesirov; Rameen Beroukhim; Calvin J. Kuo; Wolfram Goessling; William C. Hahn

Joseph Rosenbluh, Deepak Nijhawan, Andrew G. Cox, Xingnan Li, James T. Neal, Eric J. Schafer, Travis I. Zack, Xiaoxing Wang, Aviad Tsherniak, Anna C. Schinzel, Diane D. Shao, Steven E. Schumacher, Barbara A. Weir, Francisca Vazquez, Glenn S. Cowley, David E. Root, Jill P. Mesirov, Rameen Beroukhim, Calvin J. Kuo, Wolfram Goessling, and William C. Hahn* *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cell.2013.03.007


Cell | 2012

β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

Joseph Rosenbluh; Deepak Nijhawan; Andrew G. Cox; Xingnan Li; James T. Neal; Eric J. Schafer; Travis I. Zack; Xiaoxing Wang; Aviad Tsherniak; Anna C. Schinzel; Diane D. Shao; Steven E. Schumacher; Barbara A. Weir; Francisca Vazquez; Glenn S. Cowley; David E. Root; Jill P. Mesirov; Rameen Beroukhim; Calvin J. Kuo; Wolfram Goessling; William C. Hahn


Fitoterapia | 2011

Developing a library of authenticated Traditional Chinese Medicinal (TCM) plants for systematic biological evaluation — Rationale, methods and preliminary results from a Sino-American collaboration

David Eisenberg; Eric S. J. Harris; Bruce A. Littlefield; Shugeng Cao; Jane A. Craycroft; Robert Scholten; Peter E. Bayliss; Yanling Fu; Wenquan Wang; Yanjiang Qiao; Zhongzhen Zhao; Hubiao Chen; Yong Liu; Ted J. Kaptchuk; William C. Hahn; Xiaoxing Wang; Thomas J. Roberts; Caroline E. Shamu; Jon Clardy


PMC | 2014

KRAS and YAP1 Converge to Regulate EMT and Tumor Survival

Diane D. Shao; Elsa Beyer Krall; Federica Piccioni; Xiaoxing Wang; Anna C. Schinzel; Joseph Rosenbluh; Jong W. Kim; Yaara Zwang; Thomas M. Roberts; David E. Root; William C. Hahn; Arjun Bhutkar; Wen Xue; Sabina Sood; Tyler Jacks


Archive | 2011

amplification of C RKL ind uces t ra nsformation and epi dermal Growth Factor r ec eptor inh ibitor r es istance in hum an Non- s ma ll cel l lun g can cers

Hiu Wing Cheung; Jinyan Du; Jesse S. Boehm; Frank He; Barbara A. Weir; Xiaoxing Wang; Mohit Butaney; Lecia V. Sequist; Biao Luo; Jeffrey Engelman; David E. Root; Matthew Meyerson; Todd R. Golub; Pasi Antero Janne; William C. Hahn

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David E. Root

Massachusetts Institute of Technology

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