SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis

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 () and Wenyi Wei ()
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Li-Yu Huang: Shanghai Jiao Tong University
Junjie Zhao: Harvard Medical School
Hao Chen: Fudan University
Lixin Wan: Harvard Medical School
Hiroyuki Inuzuka: Harvard Medical School
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
Yihong Sun: Fudan University
Wenyi Wei: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06038-y

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