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EMBO Mol Med. 2015 Jun;7(6):831-47. doi: 10.15252/emmm.201404396.

ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.

Author information

1
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.
2
Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Erlangen, Germany.
3
Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
4
Oncotest GmbH, Institute for Experimental Oncology, Freiburg, Germany.
5
Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany.
6
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.
7
Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria.
8
Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
9
Tumorbank Comprehensive Cancer Center Freiburg and Institute of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
10
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.

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.

KEYWORDS:

HDAC inhibitor; ZEB1; cancer stem cells; drug resistance; miR‐203

PMID:
25872941
PMCID:
PMC4459821
DOI:
10.15252/emmm.201404396
[Indexed for MEDLINE]
Free PMC Article

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