ABSTRACT

DCAF13 is firstly identified as a substrate receptor of CUL4-DDB1 E3 ligase complex. This study disclosed that DCAF13 acted as a novel RNA binding protein (RBP) that contributed to triple-negative breast cancer (TNBC) metastasis. Clinical data obtained from TCGA and our collection showed that DCAF13 was closely correlated with poor clinicopathological characteristics and overall survival, which indicated DCAF13 may serve as a diagnostic marker for TNBC metastasis. Functionally, DCAF13 overexpression or suppression was sufficient to enhance or decrease breast cancer cell migration and invasion. Mechanistically, DCAF13 functioned as an RBP by binding with the AU-rich element (ARE) of DTX3 mRNA 3ʹUTR to accelerate its degradation. Moreover, we identified that DTX3 promoted the ubiquitination and degradation of NOTCH4. Finally, increased DCAF13 expression led to post-transcriptional decay of DTX3 mRNA and consequently activated of NOTCH4 signaling pathway in TNBC. In conclusion, these results identified that DCAF13 as a diagnostic marker and therapeutic target for TNBC treatment.

Abbreviation: DCAF13: DDB1 and CUL4-associated factor 13; DDB1: DNA-binding protein 1; CUL4: Cullin 4; CRL4, Cullin-ring finger ligase 4; RBP: RNA binding protein; TNBC: triple-negative breast cancer; ARE: AU-rich element; DTX3: Deltex E3 ubiquitin ligase 3; HER2: human epidermal growth factor receptor 2; ER: estrogen receptor; PR: progesterone receptor; PTEN: phosphatase and tensin homolog deleted on chromosome 10; EMT: epithelial-mesenchymal transition.

摘要

DCAF13 首次被鉴定为 CUL4-DDB1 E3 连接酶复合物的底物受体。这项研究揭示了 DCAF13 作为一种新型 RNA 结合蛋白 (RBP)，有助于三阴性乳腺癌 (TNBC) 转移。从 TCGA 和我们收集的临床数据显示 DCAF13 与较差的临床病理特征和总生存率密切相关，这表明 DCAF13 可作为 TNBC 转移的诊断标志物。在功能上，DCAF13 过表达或抑制足以增强或减少乳腺癌细胞的迁移和侵袭。从机制上讲，DCAF13 通过与 DTX3 mRNA 3ʹUTR 的富含 AU 元素 (ARE) 结合以加速其降解，从而起到 RBP 的作用。此外，我们发现 DTX3 促进了 NOTCH4 的泛素化和降解。最后，DCAF13 表达的增加导致 DTX3 mRNA 的转录后衰减，从而激活 TNBC 中的 NOTCH4 信号通路。总之，这些结果确定 DCAF13 作为 TNBC 治疗的诊断标志物和治疗靶点。

缩写： DCAF13：DDB1 和 CUL4 相关因子 13；DDB1：DNA 结合蛋白 1；CUL4：库林 4；CRL4，Cullin-环指连接酶4；RBP：RNA结合蛋白；TNBC：三阴性乳腺癌；ARE：富含 AU 的元素；DTX3：Deltex E3泛素连接酶3；HER2：人表皮生长因子受体2；ER：雌激素受体；PR：孕激素受体；PTEN：第 10 号染色体上缺失的磷酸酶和张力蛋白同源物；EMT：上皮间质转化。