The DNA Endonuclease Mus81 Regulates ZEB1 Expression and Serves as a Target of BET4 Inhibitors in Gastric Cancer.

Abstract

DNA replication and repair proteins play an important role in cancer initiation and progression by affecting genomic instability. The DNA endonuclease Mus81 is a DNA structure-specific endonuclease, which has been implicated in DNA replication and repair. In this study, we found that Mus81 promotes gastric metastasis by controlling the transcription of ZEB1, a master regulator of the epithelial-mesenchymal transition (EMT). Our results revealed that Mus81 is highly expressed in gastric cancer samples from patients and cell lines compared with their normal counterparts. Particularly, Mus81 expression positively correlated with ZEB1 expression and Mus81 overexpression was significantly associated with higher incidence of lymph node metastasis in patients. Furthermore, Mus81 promoted migration of gastric cancer cells both in vitro and in vivo We conducted a drug screen using a collection of preclinical and FDA-approved drugs and found that the BRD4 inhibitor AZD5153 inhibited the expression of Mus81 and ZEB1 by regulating the epigenetic factor Sirt5. As expected, AZD5153 treatment significantly reduced the migration of gastric cancer cells overexpressing Mus81 in vitro and in vivo Collectively, we show that Mus81 is a regulator of ZEB1 and promotes metastasis in gastric cancer. Importantly, we demonstrate that the BRD4 inhibitor AZD5153 can potentially be used as an effective antimetastasis drug because of its effect on Mus81.

• Authors: Yuping Yin, Weizhen Liu, Qian Shen, Peng Zhang, Lulu Wang, Ruikang Tao, Hang Li, Xianxiong Ma, Xiangyu Zeng, Jae-Ho Cheong, Shumei Song, Jaffer A Ajani, Gordon B Mills, Kaixiong Tao, Guang Peng
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 8 Pg. 1439-1450 (08 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31142662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• BRD4 protein, human
• Cell Cycle Proteins
• DNA-Binding Proteins
• Heterocyclic Compounds, 2-Ring
• Piperazines
• Pyrazoles
• Pyridazines
• Transcription Factors
• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• AZD5153
• Endonucleases
• MUS81 protein, human
• SIRT5 protein, human
• Sirtuins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Binding Sites
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Drug Discovery
• Drug Screening Assays, Antitumor
• Endonucleases (genetics, metabolism)
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 2-Ring (pharmacology)
• Humans
• Lymphatic Metastasis
• Mice
• Piperazines (pharmacology)
• Protein Binding
• Pyrazoles
• Pyridazines
• Sirtuins (metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Transcription Factors (metabolism)
• Zinc Finger E-box-Binding Homeobox 1 (genetics, metabolism)