A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis
A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis
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PAK5-DNPEP-USP4 轴决定乳腺癌的生长和转移
DOI：
10.1002/ijc.32523
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发表时间：
2019-06-20
影响因子：
6.4
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Geng, Nanxi;Li, Yang;Li, Feng
尽管p21激活激酶5（PAK 5）在临床上与多种癌症的进展相关，但其在乳腺癌中的生物学功能在很大程度上仍然未知。在这里，我们揭示了PAK 5-乙酰氨基肽酶（DNPEP）-泛素特异性蛋白酶4（USP 4）轴参与乳腺癌的进展。我们发现PAK 5与DNPEP在丝氨酸119处相互作用并磷酸化DNPEP。在功能上，我们证明DNPEP过表达抑制乳腺癌细胞增殖和侵袭，并限制小鼠乳腺癌的生长和转移。此外，我们确定USP 4作为PAK 5-DNPEP通路的下游靶点; DNPEP介导USP 4下调。重要的是，我们证实DNPEP表达在乳腺癌组织中经常下调，并且与PAK 5和USP 4表达呈负相关。PAK 5通过泛素-蛋白酶体途径降低DNPEP丰度。一致地，临床乳腺癌标本的分析显示PAK 5和USP 4水平显著增加，并且PAK 5和USP 4表达较高与乳腺癌患者生存率较差之间存在关联。这些发现表明PAK 5引发的信号传导在乳腺癌进展中的关键作用。
Although clinically associated with the progression of multiple cancers, the biological function of p21-activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5-aspartyl aminopeptidase (DNPEP)-ubiquitin-specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5-elicited signaling in breast cancer progression.