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- Title
A PAK5–DNPEP–USP4 axis dictates breast cancer growth and metastasis.
- Authors
Geng, Nanxi; Li, Yang; Zhang, Wenyu; Wang, Fei; Wang, Xu; Jin, Zining; Xing, Yao; Li, Danni; Zhang, Hongyan; Li, Yanshu; Li, Xiaodong; Cheng, Maosheng; Jin, Feng; Li, Feng
- 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. What's new? Increasing lines of evidence suggest that PAK5 is an oncogenic protein that is commonly overexpressed in many cancer tissues and plays multiple functions in cancer progression. However, the underlying molecular mechanisms and the biological significance of PAK5 in breast cancer remain to be fully explored. Here, the authors reveal that DNPEP links the upstream PAK5 kinase to the downstream target USP4 through a phosphorylation‐based regulatory mechanism in malignant breast cancer. Moreover, they identify an association between elements of the PAK5‐DNPEP‐USP4 pathway and clinicopathological features in breast cancer patients, altogether providing potential prognostic markers and therapeutic targets for breast cancer intervention.
- Subjects
METASTATIC breast cancer; CANCER cell proliferation; ONCOGENIC proteins; BREAST cancer; CANCER invasiveness
- Publication
International Journal of Cancer, 2020, Vol 146, Issue 4, p1139
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.32523