Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.

表观遗传可塑性是驱动转移的关键因素。在这里，我们发现编码泛素连接酶亚基 FBXL7 的基因启动子在晚期前列腺癌和胰腺癌中高度甲基化，与FBXL7 mRNA 和蛋白质水平降低相关。低FBXL7 mRNA 水平预示着胰腺癌和前列腺癌患者的生存率较差。 FBXL7 在 Ser 104 位点磷酸化后介导活性 c-SRC 的泛素化和蛋白酶体降解。DNA 去甲基化剂地西他滨可恢复 FBXL7 表达，并以 c-SRC 依赖性方式限制上皮间质转化和细胞侵袭。在体内，FBXL7耗尽的癌细胞形成具有高转移负担的肿瘤。沉默 c-SRC 或使用 c-SRC 抑制剂达沙替尼治疗并去除 FBXL7 可预防转移。此外，地西他滨以 FBXL7 依赖性方式减少前列腺癌细胞和胰腺癌细胞的转移。总的来说，这项研究表明FBXL7是一种转移抑制基因，并提出了对抗胰腺癌细胞和前列腺癌细胞转移扩散的治疗策略。