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PAK4 phosphorylating RUNX1 promotes ERα-positive breast cancer-induced osteolytic bone destruction

Lina Tang1, Yunling Gao1, Yongqi Song1

  • 1Department of Cell Biology, Key Laboratory of Cell Biology of National Health Commission of the PRC, and Key Laboratory of Medical Cell Biology of Ministry of Education of the PRC, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning, China.

International Journal of Biological Sciences
|June 19, 2020
PubMed

Insights

Nuclear PAK4 promotes osteoclast formation and bone destruction in ERα-positive breast cancer by phosphorylating RUNX1. This finding suggests PAK4 as a potential therapeutic target for breast cancer bone metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Bone Biology

Background:

  • The role of nuclear PAK4 in ERα-positive breast cancer's osteolytic bone destruction is not well understood.
  • Osteolytic bone destruction is a significant complication of breast cancer metastasis.

Purpose of the Study:

  • To elucidate the biological function of nuclear PAK4 in ERα-positive breast cancer-induced osteolytic bone destruction.
  • To identify the molecular mechanisms by which nuclear PAK4 contributes to bone metastasis.

Main Methods:

  • Investigated the interaction and phosphorylation of RUNX1 by PAK4.
  • Analyzed RUNX1 subcellular localization in breast cancer bone metastasis tissues.
  • Utilized a mouse model of orthotopic breast cancer bone metastasis to assess osteolytic bone damage.

Main Results:

  • Nuclear PAK4 phosphorylates RUNX1 at Thr-207, promoting its cytoplasmic localization.
  • RUNX1 phosphorylation by PAK4 influences interactions with SIN3A/HDAC1 and PRMT1.
  • PAK4-mediated RUNX1 phosphorylation drives osteoclastogenesis and osteolytic bone destruction in vivo.

Conclusions:

  • Nuclear PAK4 promotes osteoclastogenesis and osteolytic bone destruction in ERα-positive breast cancer via RUNX1 phosphorylation.
  • PAK4 is a potential therapeutic target for managing breast cancer bone metastasis and associated bone destruction.
Keywords:
PAK4RUNX1osteolytic bone destructionphosphorylation

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