Journal Article

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

Culig, Zoran, Stemmler, Marc P, Bronsert, Peter, Küsters, Simon, Wellner, Ulrich, Mock, Kerstin, Schüler, Julia, Burk, Ulrike, Lehmann, Waltraut, Berthold, Maria, Keck, Tobias, Weber, Anika, Preca, Bogdan‐Tiberius, Meidhof, Simone, Ruh, Manuel, Lübbert, Michael, Brabletz, Simone, Brabletz, Thomas, Puhr, Martin, Hopt, Ulrich T

2015

Overview

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. Synopsis Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells. Strategy to counteract the well‐known cancer‐promoting functions of the EMT inducer ZEB1. Identification of the stemness‐inhibiting microRNA miR‐203 as major ZEB1 target inducing drug sensitivity. Identification of the class I HDAC inhibitor mocetinostat as drug to interfere with ZEB1 function and overcome ZEB1‐associated drug resistance. Mocetinostat has better effects in combination with chemotherapeutics compared to other HDACis, such as SAHA. Blueprint for further drug screens with reduction in ZEB1 function as major readout. Graphical Abstract Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells.

• Publisher: Nature Publishing Group UK,BlackWell Publishing Ltd,Springer Nature
• Subject: Antineoplastic Agents - pharmacology / Benzamides - metabolism / cancer stem cells / Cell Line, Tumor / Drug Resistance / EMBO03 / EMBO09 / Epithelial-Mesenchymal Transition - drug effects / HDAC inhibitor / Histone Deacetylase Inhibitors - metabolism / Homeodomain Proteins - metabolism / Humans / MicroRNAs - biosynthesis / miR‐203 / Pyrimidines - metabolism / Research Article / Transcription Factors - metabolism / ZEB1 / Zinc Finger E-box-Binding Homeobox 1