Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, The Alexandria Center for Life Science, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, The Alexandria Center for Life Science, New York, NY 10016, USA.
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Cell Rep. 2021 Oct 19;37(3):109870. doi: 10.1016/j.celrep.2021.109870.
FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1 promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and -2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer.
FBXO31 是多种 CUL1-RING 泛素连接酶（CRL1）复合物的底物受体。在这里，我们表明，在人类前列腺癌中，低 FBXO31 mRNA 水平与高术前前列腺特异性抗原（PSA）水平和 Gleason 分级相关。从机制上讲，泛素连接酶 CRL1 促进双特异性磷酸酶 DUSP6 的泛素化介导降解，该磷酸酶可使细胞外信号调节激酶-1 和 -2（ERK1/2）去磷酸化并失活。FBXO31 的耗竭稳定了 DUSP6，抑制了 ERK 信号转导，并激活了 PI3K-AKT 信号级联。此外，FBXO31 的缺失促进了前列腺癌小鼠原位模型中的肿瘤发展。用 DUSP6 的小分子抑制剂 BCI 治疗可抑制 AKT 激活并防止肿瘤形成，表明 FBXO31 肿瘤抑制活性依赖于 DUSP6。总之，我们的研究强调了 FBXO31-DUSP6 轴在调节 ERK 和 PI3K-AKT 介导的信号通路中的相关性，以及其在前列腺癌中的治疗潜力。
