PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer

Cell Rep. 2021 Dec 21;37(12):110127. doi: 10.1016/j.celrep.2021.110127.

Abstract

P21-activated kinase 5 (PAK5) plays an important role in tumors. However, the functional role of PAK5 in mammary tumorigenesis in vivo remains unclear. Here, we show that PAK5 deficiency represses MMTV-PyVT-driven breast tumorigenesis. DEAD-box RNA helicase 5 (DDX5) is a substrate of PAK5, which is phosphorylated on threonine 69. PAK5-mediated DDX5 phosphorylation promotes breast cancer cell proliferation and metastasis. The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. Finally, we verify decreased expression of DDX5 phosphorylation and sumoylation and mature miR-10b in PAK5-/-/MMTV-PyVT transgenic mice. Our findings provide insights into the function of PAK5 in microRNA (miRNA) biogenesis, which might be a potential therapeutic target for breast cancer.

Keywords: DDX5; MMTV-PyVT mice; PAK5; miRNA processing; phosphorylation; sumoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / metabolism*
  • Phosphorylation
  • RNA-Binding Proteins / metabolism
  • Ribonuclease III / metabolism
  • Signal Transduction
  • Sumoylation*
  • Tumor Cells, Cultured
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*

Substances

  • MIRN10 microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • p21-Activated Kinases
  • Ribonuclease III
  • Ddx5 protein, human
  • DEAD-box RNA Helicases