The DNA endonuclease Mus81 regulates ZEB1 expression and serves as a target of BET4 inhibitors in gastric cancer

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 Mills, Kaixiong Tao, Guang Peng

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)1439-1450
    Number of pages12
    JournalMolecular cancer therapeutics
    Volume18
    Issue number8
    DOIs
    StatePublished - Jan 1 2019

    Fingerprint

    Deoxyribonuclease I
    Stomach Neoplasms
    Neoplasm Metastasis
    DNA Replication
    DNA Repair
    Pharmaceutical Preparations
    Epithelial-Mesenchymal Transition
    Genomic Instability
    Endonucleases
    Epigenomics
    Stomach
    Lymph Nodes
    Cell Line
    DNA
    Incidence
    Neoplasms
    Proteins
    In Vitro Techniques
    Therapeutics

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    The DNA endonuclease Mus81 regulates ZEB1 expression and serves as a target of BET4 inhibitors in gastric cancer. / Yin, Yuping; Liu, Weizhen; Shen, Qian; Zhang, Peng; Wang, Lulu; Tao, Ruikang; Li, Hang; Ma, Xianxiong; Zeng, Xiangyu; Cheong, Jae Ho; Song, Shumei; Ajani, Jaffer A.; Mills, Gordon; Tao, Kaixiong; Peng, Guang.

    In: Molecular cancer therapeutics, Vol. 18, No. 8, 01.01.2019, p. 1439-1450.

    Research output: Contribution to journalArticle

    Yin, Y, Liu, W, Shen, Q, Zhang, P, Wang, L, Tao, R, Li, H, Ma, X, Zeng, X, Cheong, JH, Song, S, Ajani, JA, Mills, G, Tao, K & Peng, G 2019, 'The DNA endonuclease Mus81 regulates ZEB1 expression and serves as a target of BET4 inhibitors in gastric cancer', Molecular cancer therapeutics, vol. 18, no. 8, pp. 1439-1450. https://doi.org/10.1158/1535-7163.MCT-18-0833
    Yin, Yuping ; Liu, Weizhen ; Shen, Qian ; Zhang, Peng ; Wang, Lulu ; Tao, Ruikang ; Li, Hang ; Ma, Xianxiong ; Zeng, Xiangyu ; Cheong, Jae Ho ; Song, Shumei ; Ajani, Jaffer A. ; Mills, Gordon ; Tao, Kaixiong ; Peng, Guang. / The DNA endonuclease Mus81 regulates ZEB1 expression and serves as a target of BET4 inhibitors in gastric cancer. In: Molecular cancer therapeutics. 2019 ; Vol. 18, No. 8. pp. 1439-1450.
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    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.",
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    AU - Wang, Lulu

    AU - Tao, Ruikang

    AU - Li, Hang

    AU - Ma, Xianxiong

    AU - Zeng, Xiangyu

    AU - Cheong, Jae Ho

    AU - Song, Shumei

    AU - Ajani, Jaffer A.

    AU - Mills, Gordon

    AU - Tao, Kaixiong

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