A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis

Int J Cancer. 2020 Feb 15;146(4):1139-1151. doi: 10.1002/ijc.32523. Epub 2019 Jun 20.

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.

Keywords: DNPEP; PAK5; USP4; breast cancer progression; phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology*
  • Cell Growth Processes / physiology
  • Female
  • Glutamyl Aminopeptidase / metabolism*
  • HEK293 Cells
  • Heterografts
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Phosphorylation
  • Signal Transduction
  • Ubiquitin-Specific Proteases / metabolism*
  • p21-Activated Kinases / metabolism*

Substances

  • USP4 protein, human
  • PAK5 protein, human
  • p21-Activated Kinases
  • Glutamyl Aminopeptidase
  • Ubiquitin-Specific Proteases