Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, 200240, Shanghai, China.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Nat Commun. 2018 Sep 3;9(1):3569. doi: 10.1038/s41467-018-06038-y.
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 SCF. 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.
Brg1/SMARCA4 作为多亚基 SWI/SNF 染色质重塑复合物的 ATP 酶和解旋酶催化亚基，在调节染色质结构和基因转录中起着关键作用。然而，调节 Brg1 蛋白稳定性及其对肿瘤发生的生理贡献的上游信号通路在很大程度上仍未被揭示。在这里，我们报告 Brg1 是 SCF 的真正泛素底物。我们揭示 CK1δ 在 Ser31/Ser35 残基处磷酸化 Brg1，以促进 Brg1 与 FBW7 的结合，导致泛素介导的降解。与 FBW7 在人类胃癌中作为肿瘤抑制因子的作用一致，我们在人类胃癌临床样本中发现 FBW7 和 Brg1 表达之间呈负相关。在机制上，我们发现胃癌细胞中 Brg1 的稳定会抑制 E-钙黏蛋白的表达，从而促进胃癌转移。因此，这个以前未知的 FBW7/Brg1 信号通路为靶向 FBW7 缺陷型人类胃癌中的 Brg1 提供了分子基础和理论依据。
