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

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.

• Authors: Yang Li, Yao Xing, Xu Wang, Bingtao Hu, Xin Zhao, Hongyan Zhang, Fuyi Han, Nanxi Geng, Fei Wang, Yanshu Li, Jiabin Li, Feng Jin, Feng Li
• Journal: Cell reports (Cell Rep) Vol. 37 Issue 12 Pg. 110127 (12 21 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34936874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Animals
• Breast Neoplasms (genetics, metabolism)
• Carcinogenesis
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DEAD-box RNA Helicases (genetics, 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, metabolism)