Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea.
Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea.
Oncogene. 2018 Oct;37(43):5794-5809. doi: 10.1038/s41388-018-0372-3. Epub 2018 Jul 4.
Understanding the molecular mechanisms that underlie the aggressive behavior and relapse of breast cancer may help in the development of novel therapeutic interventions. CUB-domain-containing protein 1 (CDCP1), a transmembrane adaptor protein, is highly maintained and required in the context of cellular metastatic potential in triple-negative breast cancer (TNBC). For this reason, gene expression levels of CDCP1 have been considered as a prognostic marker in TNBC. However, not rarely, transcript levels of genes do not reflect always the levels of proteins, due to the post-transcriptional regulation. Here we show that miR-17/20a control the FBXL14 E3 ligase, establishing FBXL14 as an upstream regulator of the CDCP1 pathway. FBXL14 acts as an novel interaction partner of CDCP1, and facilitates its ubiquitination and proteasomal degradation with an enhanced capacity to suppress CDCP1 protein stability that eventually prevents CDCP1 target genes involved in breast cancer metastasis. Our findings first time uncovers the regulatory mechanism of CDCP-1 protein stabilization, more predictable criteria than gene expression levels for prognosis of breast cancer patients.
了解乳腺癌侵袭性行为和复发的分子机制可能有助于开发新的治疗干预措施。CUB 结构域包含蛋白 1（CDCP1）是一种跨膜衔接蛋白，在三阴性乳腺癌（TNBC）的细胞转移潜能方面高度维持和必需。出于这个原因，CDCP1 的基因表达水平被认为是 TNBC 的预后标志物。然而，由于转录后调控，基因的转录水平并不总是反映蛋白质的水平。在这里，我们表明 miR-17/20a 控制 FBXL14 E3 连接酶，将 FBXL14 确立为 CDCP1 途径的上游调节剂。FBXL14 作为 CDCP1 的新型相互作用伙伴，促进其泛素化和蛋白酶体降解，增强抑制 CDCP1 蛋白稳定性的能力，最终防止 CDCP1 参与乳腺癌转移的靶基因。我们的研究结果首次揭示了 CDCP-1 蛋白稳定的调节机制，这是比基因表达水平更能预测乳腺癌患者预后的指标。
