A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis.
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| Abstract |
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.
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| Authors | Nanxi Geng, Yang Li, Wenyu Zhang, Fei Wang, Xu Wang, Zining Jin, Yao Xing, Danni Li, Hongyan Zhang, Yanshu Li, Xiaodong Li, Maosheng Cheng, Feng Jin, Feng Li |
| Journal | International journal of cancer (Int J Cancer) Vol. 146 Issue 4 Pg. 1139-1151 (02 15 2020) ISSN: 1097-0215 [Electronic] United States |
| PMID | 31219614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. |
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