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Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis

Xiaofeng Jin1,2, Shi Qing3, Qian Li1,2

  • 1The Affiliated Hospital of Medical School, Ningbo University, Ningbo 315020, China.

Nucleic Acids Research
|June 16, 2021
PubMed

Insights

Prostate cancer mutations in Speckle-type Poz protein (SPOP) cause genomic instability. DNA damage triggers SPOP to enhance DNA repair via the HIPK2-HP1γ pathway, but mutations disrupt this process.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Speckle-type Poz protein (SPOP) is frequently mutated in prostate cancer, leading to genomic instability.
  • The mechanisms underlying SPOP mutation-driven genomic instability remain largely unknown.

Purpose of the Study:

  • To elucidate the role of SPOP in DNA damage response and its implications in prostate cancer.
  • To investigate how SPOP mutations affect genomic stability.

Main Methods:

  • Investigated SPOP phosphorylation at Ser119 by ATM kinase upon DNA damage.
  • Assessed SPOP's interaction with homeodomain-interacting protein kinase 2 (HIPK2).
  • Analyzed HIPK2 ubiquitination and its effect on HP1γ phosphorylation and dissociation from H3K9me3.

Main Results:

  • DNA damage induces ATM-mediated SPOP phosphorylation, enhancing SPOP-HIPK2 binding and nondegradative HIPK2 ubiquitination.
  • This process increases HIPK2's phosphorylation of HP1γ, promoting HP1γ dissociation from H3K9me3 for DNA repair.
  • Prostate cancer-associated SPOP mutations abrogate SPOP's function in the HIPK2-HP1γ DNA repair pathway.

Conclusions:

  • SPOP plays a critical role in DNA damage repair through the HIPK2-HP1γ axis.
  • SPOP mutations disrupt this pathway, contributing to genomic instability in prostate cancer.
  • Understanding this mechanism offers new therapeutic targets for prostate cancer.

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