@article{f9330930693e401494d07cee62f2cee9,
title = "Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer",
abstract = "Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.",
author = "Sakari Vanharanta and Weiping Shu and Fabienne Brenet and {Ari Hakimi}, A. and Adriana Heguy and Agnes Viale and Reuter, {Victor E.} and Hsieh, {James J.D.} and Scandura, {Joseph M.} and Joan Massagu{\'e}",
note = "Funding Information: We thank members of the Massagu{\'e} lab for discussion, J. Brooks (Stanford University, California) for clinical annotations, W. Krek (ETH, Swiss Federal Institute of Technology, Zurich, Switzerland) for CXCR4 promoter constructs and C. David and S. Malladi for critical review of the manuscript. Gene expression profiling and high-throughput sequencing were done at the Memorial Sloan-Kettering Cancer Center (MSKCC) Genomics Core Facility, immunohistochemical staining was done at the MSKCC Molecular Cytology Core Facility, and DNA methylation analysis, RNA analysis of clinical samples and Sanger sequencing were done at the MSKCC Geoffrey Beene Translational Oncology Core Facility. The GSE2109 dataset was provided by the International Genomics Consortium and Expression Project for Oncology. S.V. received postdoctoral support from the Maud Kuistila Memorial Foundation, the Emil Aaltonen Foundation, the Paulo Foundation, the Orion-Farmos Research Foundation, the Instrumentarium Science Foundation, The Finnish Medical Foundation and the Academy of Finland. J.M. is an investigator of the Howard Hughes Medical Institute.",
year = "2013",
month = jan,
doi = "10.1038/nm.3029",
language = "English",
volume = "19",
pages = "50--56",
journal = "Nature medicine",
issn = "1078-8956",
number = "1",
}