title: A bivalent promoter contributes to stress-induced plasticity of CXCR4 in Ewing sarcoma.
abstract: Tumor heterogeneity is a major impediment to cancer cures. Tumor cell heterogeneity can arise by irreversible genetic mutation, as well as by non-mutational mechanisms, which can be reversibly modulated by the tumor microenvironment and the epigenome. We recently reported that the chemokine receptor CXCR4 is induced in Ewing sarcoma cells in response to microenvironmental stress. In the current study, we investigated plasticity of CXCR4 expression in vivo and assessed whether CXCR4 impacts on tumor growth. Our studies showed that Ewing sarcoma cells convert between CXCR4 negative and CXCR4 positive states in vivo and that positive cells are most abundant adjacent to areas of necrosis. In addition, tumor volumes directly correlated with CXCR4 expression supporting a role for CXCR4 in growth promotion. Mechanistically, our results show that, in ambient conditions where CXCR4 expression is low, the CXCR4 promoter exists in a poised, bivalent state with simultaneous enrichment of both activating (H3K4me3) and repressive (H3K27me3) post-translational histone modifications. In contrast, when exposed to stress, CXCR4 negative cells lose the H3K27me3 mark. This loss of promoter bivalency is associated with CXCR4 upregulation. These studies demonstrate that stress-dependent plasticity of CXCR4 is, in part, mediated by epigenetic plasticity and a bivalent promoter.
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Krook
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Allegra G
authors.initials: AG
authors.lastname: Hawkins
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rajiv M
authors.initials: RM
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Lucas
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Raelene
authors.initials: R
authors.lastname: Van Noord
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.affiliation: Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Lawlor
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002469:Cell Separation; D002843:Chromatin / Q000737:chemistry; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009336:Necrosis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D019718:Receptors, CXCR4 / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; D002843:Chromatin; D006657:Histones; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins
keywords: CXCR4; Ewing sarcoma; epigenetics; plasticity