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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Sakari
authors.initials: S
authors.lastname: Vanharanta
authors.forename: Weiping
authors.initials: W
authors.lastname: Shu
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brenet
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: James J-D
authors.initials: JJ
authors.lastname: Hsieh
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: C527276:CXCR4 protein, human; C084539:CYTIP protein, human; D006657:Histones; D051793:Hypoxia-Inducible Factor 1; D019718:Receptors, CXCR4; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; D051794:Von Hippel-Lindau Tumor Suppressor Protein