Neoplasma. 2018;65(2):201-209. doi: 10.4149/neo_2018_170228N149.
Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation. Forced overexpression of FBXW7 could decrease the level of MTDH protein, and inhibition of endogenous FBXW7 expression remarkably increases the MTDH protein abundance. More importantly, overexpression of FBXW7 could lead to proliferation arrest and apoptosis in breast cancer cells through targeting MTDH degradation. These data suggest that FBXW7, a tumor suppressor, inhibits breast cancer cell prolifera- tion and promotes apoptosis at least partially through targeting MTDH for proteolysis. This new regulatory mechanism of MTDH by FBXW7 represents a new pathway for malignant phenotype turnover in human breast cancer.
MTDH（metadherin）是一种癌蛋白，在多种人类癌中高表达，是重要的遗传决定因子，调控肿瘤发生过程中的多种事件。MTDH 通过激活众多信号通路促进乳腺癌细胞增殖和致瘤性。目前，调控 MTDH 表达的机制尚不清楚。本研究发现，E3 泛素连接酶的组成部分 FBXW7 可靶向 MTDH 进行泛素介导的降解。FBXW7 的强制过表达可降低 MTDH 蛋白水平，而内源性 FBXW7 表达的抑制则显著增加 MTDH 蛋白丰度。更重要的是，通过靶向 MTDH 降解，FBXW7 的过表达可导致乳腺癌细胞增殖停滞和凋亡。这些数据表明，肿瘤抑制因子 FBXW7 通过靶向 MTDH 进行蛋白水解，至少部分抑制了乳腺癌细胞的增殖并促进了凋亡。FBXW7 对 MTDH 的这种新的调控机制代表了人类乳腺癌恶性表型转变的新途径。
