ZEB 1‐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.

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…Besides preventing ZEB-mediated repression of CDH1 by inhibiting the Class I HDACs corepressors, the effect of LBH589 is partially mediated by inhibition of ZEB expression (Rhodes et al 2014). The expression of ZEB1 is also reduced in pancreatic cancer cells after mocetinostat treatment that sensitizes the undifferentiated, ZEB1-expressing cancer cells for chemotherapy (Meidhof et al 2015). These findings indicate the therapeutic potential of inhibition of Class I HDACs in targeting EMT and metastasis of cancer cells.…”

Cancer Stem Cells: Basic Concepts and Therapeutic Implications

“…EMT cells are usually slow cycling and have lower levels of ROS, and EMT TFs may induce other important functional properties directly controlling resistance to therapy by regulating apoptosis, autophagy, or other mechanisms (201). Zeb1-induced EMT and tumor stemness confer resistance to therapy in different tumor types (185,(202)(203)(204). Ionizing radiation induces activation of Atm, which phosphorylates and stabilizes Zeb1 in response to DNA damage.…”

“…Zeb1, through interaction with Ups7, activates Chk1, promoting DNA repair and resistance to radiation (205). As Zeb1 is regulated by miR-203, which itself is regulated by epigenetic mechanisms, treatment by the histone deacetylase inhibitor mocetinostat restores miR-203 expression, represses Zeb1, and restores drug sensitivity (203). Loss of miR-205 is associated with tumor relapse in breast cancer patients.…”

Chemoresistance in pancreatic cancer: Emerging concepts

“…ZEB1 regulates stemness and chemoresistance by the epigenetic silencing of miR-203. Treatment with mocetinostat, a class I histone deacetylase inhibitor, restored miR-203 function, which led to chemosensitization and a loss of stem cell characteristics (29). A previous study demonstrated that metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1), a long non-coding (lnc) RNA, may increase proportions of pancreatic cancer stem cells, increase self-renewal and decrease chemosensitivity (30).…”