A Noncanonical Role of Fructose-1, 6-Bisphosphatase 1 Is Essential for Inhibition of Notch1 in Breast Cancer
A Noncanonical Role of Fructose-1, 6-Bisphosphatase 1 Is Essential for Inhibition of Notch1 in Breast Cancer
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DOI：
10.1158/1541-7786.mcr-19-0842
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发表时间：
2020-05-01
影响因子：
5.2
通讯作者：
Yu, Zhenhai
中科院分区：
文献类型：
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作者：
Lu, Chao;Ren, Chune;Yu, Zhenhai
乳腺癌是全世界女性死亡的主要原因，但乳腺肿瘤发生的潜在机制仍不清楚。果糖-1, 6-二磷酸酶 1 (FBP1) 是糖异生过程中的限速酶，最近被证明是乳腺癌的肿瘤抑制因子。然而，FBP1 作为乳腺癌肿瘤抑制因子的机制仍有待探索。在这里，我们发现 FBP1 在乳腺癌细胞中与 Notch1 结合。此外，FBP1 增强了 Notch1 的泛素化，进一步通过 FBXW7 途径导致蛋白酶体降解。此外，我们发现FBP1显着抑制乳腺癌细胞中Notch1的反式激活。从功能上来说，Notch1 参与体内和体外 FBP1 介导的乳腺癌细胞的肿瘤发生。总而言之，这些发现表明FBP1通过调节Notch1通路抑制乳腺肿瘤发生，凸显FBP1作为乳腺癌的潜在治疗靶点。意义：我们证明FBP1是乳腺癌中Notch1的新型调节剂。
Breast cancer is a leading cause of death in women worldwide, but the underlying mechanisms of breast tumorigenesis remain unclear. Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor in breast cancer. However, the mechanisms of FBP1 as a tumor suppressor in breast cancer remain to be explored. Here we showed that FBP1 bound to Notch1 in breast cancer cells. Moreover, FBP1 enhanced ubiquitination of Notch1, further leading to proteasomal degradation via FBXW7 pathway. In addition, we found that FBP1 significantly repressed the transactivation of Notch1 in breast cancer cells. Functionally, Notch1 was involved in FBP1-mediated tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these findings indicate that FBP1 inhibits breast tumorigenesis by regulating Notch1 pathway, highlighting FBP1 as a potential therapeutic target for breast cancer.Implications: We demonstrate FBP1 as a novel regulator for Notch1 in breast cancer.