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SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis

Author

Listed:
  • Li-Yu Huang

    (Shanghai Jiao Tong University
    Harvard Medical School
    Chinese National Human Genome Center at Shanghai)

  • Junjie Zhao

    (Harvard Medical School
    Fudan University)

  • Hao Chen

    (Fudan University)

  • Lixin Wan

    (Harvard Medical School
    H. Lee Moffitt Cancer Center and Research Institute)

  • Hiroyuki Inuzuka

    (Harvard Medical School
    Tohoku University Graduate School of Dentistry)

  • Jianping Guo

    (Harvard Medical School)

  • Xuhong Fu

    (Shanghai Jiao Tong University)

  • Yangyang Zhai

    (Shanghai Jiao Tong University)

  • Zhaoning Lu

    (Shanghai Jiao Tong University)

  • Xuefei Wang

    (Fudan University)

  • Ze-Guang Han

    (Shanghai Jiao Tong University
    Chinese National Human Genome Center at Shanghai)

  • Yihong Sun

    (Fudan University)

  • Wenyi Wei

    (Harvard Medical School)

Abstract

Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCFFBW7. We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. In keeping with a tumor suppressive role of FBW7 in human gastric cancer, we find an inverse correlation between FBW7 and Brg1 expression in human gastric cancer clinical samples. Mechanistically, we find that stabilization of Brg1 in gastric cancer cells suppresses E-cadherin expression, subsequently promoting gastric cancer metastasis. Hence, this previously unknown FBW7/Brg1 signaling axis provides the molecular basis and the rationale to target Brg1 in FBW7-compromised human gastric cancers.

Suggested Citation

  • Li-Yu Huang & Junjie Zhao & Hao Chen & Lixin Wan & Hiroyuki Inuzuka & Jianping Guo & Xuhong Fu & Yangyang Zhai & Zhaoning Lu & Xuefei Wang & Ze-Guang Han & Yihong Sun & Wenyi Wei, 2018. "SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06038-y
    DOI: 10.1038/s41467-018-06038-y
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    Cited by:

    1. Yalei Wen & Hui Wang & Xiao Yang & Yingjie Zhu & Mei Li & Xiuqing Ma & Lei Huang & Rui Wan & Caishi Zhang & Shengrong Li & Hongling Jia & Qin Guo & Xiaoyun Lu & Zhengqiu Li & Xiangchun Shen & Qiushi Z, 2024. "Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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