title: The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (β-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by β-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and anti-apoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma.
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, CIBERehd, Barcelona 08036, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.affiliation: 1] Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, CIBERehd, Barcelona 08036, Spain [2] Master Program in Biomedical Research, University Pompeu Fabra, Barcelona 08002, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Fanlo
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, CIBERehd, Barcelona 08036, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Siles
authors.affiliation: Department of Pathology and Group of Cancer Genomics, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Montes-Moreno
authors.affiliation: Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona 08036, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moros
authors.affiliation: 1] Department of Internal Medicine, Hospital Clinic, Barcelona 08036, Spain [2] CIBERobn, ISCIII, Santiago de Compostela 15706, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Chiva-Blanch
authors.affiliation: 1] Department of Internal Medicine, Hospital Clinic, Barcelona 08036, Spain [2] CIBERobn, ISCIII, Santiago de Compostela 15706, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Estruch
authors.affiliation: Department of Pathology, Hospital Clinic, Barcelona 08036, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona 08036, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Research Lab for Pediatrics and Nephrology, Hungarian Academy of Sciences, Semmelweis University, 1st Department of Pediatrics, Budapest 1083, Hungary.
authors.forename: B
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Hematopathology Unit, Hospital Clinic, IDIBAPS, Barcelona 08036, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Roué
authors.affiliation: 1] Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, CIBERehd, Barcelona 08036, Spain [2] James Graham Brown Cancer Center, Louisville, KY 40202, USA [3] ICREA, Barcelona 08010, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Postigo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011714:Pyrans / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000095662:Polyether Polyketides
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D011714:Pyrans; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C486307:ZEB1 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides