title: ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.
abstract: Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Simone
authors: S
authors: Meidhof
authors: Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany.
authors: Simone
authors: S
authors: Brabletz
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Waltraut
authors: W
authors: Lehmann
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Bogdan-Tiberius
authors: BT
authors: Preca
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Kerstin
authors: K
authors: Mock
authors: Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany.
authors: Manuel
authors: M
authors: Ruh
authors: Oncotest GmbH, Institute for Experimental Oncology, Freiburg, Germany.
authors: Julia
authors: J
authors: Schüler
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
authors: Maria
authors: M
authors: Berthold
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
authors: Anika
authors: A
authors: Weber
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
authors: Ulrike
authors: U
authors: Burk
authors: Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany German Cancer Consortium (DKTK), Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Michael
authors: M
authors: Lübbert
authors: Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria.
authors: Martin
authors: M
authors: Puhr
authors: Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria.
authors: Zoran
authors: Z
authors: Culig
authors: Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
authors: Ulrich
authors: U
authors: Wellner
authors: Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
authors: Tobias
authors: T
authors: Keck
authors: Tumorbank Comprehensive Cancer Center Freiburg and Institute of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors: Peter
authors: P
authors: Bronsert
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
authors: Simon
authors: S
authors: Küsters
authors: Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
authors: Ulrich T
authors: UT
authors: Hopt
authors: Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany.
authors: Marc P
authors: MP
authors: Stemmler
authors: Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany German Cancer Consortium (DKTK), Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany thomas.brabletz@fau.de.
authors: Thomas
authors: T
authors: Brabletz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000378:metabolism*; D045744:Cell Line, Tumor; D004351:Drug Resistance; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis; D011743:Pyrimidines / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D011743:Pyrimidines; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C523184:mocetinostat
keywords: HDAC inhibitor; ZEB1; cancer stem cells; drug resistance; miR‐203