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SRPK1 acetylation modulates alternative splicing to regulate cisplatin resistance in breast cancer cells

Cheng Wang1, Zhihong Zhou2, Charannya Sozheesvari Subhramanyam1

  • 1Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 4 Medical Drive, Singapore, Singapore, 117594.

Communications Biology
|May 29, 2020
PubMed

Insights

Tip60 acetylation of serine-arginine protein kinase 1 (SRPK1) impacts breast cancer chemotherapy sensitivity. Enhancing SRPK1 acetylation or inhibiting its activity can re-sensitize cisplatin-resistant cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Platinum-based chemotherapy, including cisplatin, is a cornerstone in breast cancer treatment.
  • Drug resistance significantly limits the efficacy of these chemotherapies.
  • Pre-mRNA alternative splicing, regulated by kinases like serine-arginine protein kinase 1 (SRPK1), influences drug responsiveness, but SRPK1's role in resistance is debated.

Purpose of the Study:

  • To investigate the role of SRPK1 in cisplatin resistance in breast cancer.
  • To explore the association between SRPK1 modification (acetylation and phosphorylation) and chemotherapy sensitivity.
  • To identify potential therapeutic strategies to overcome cisplatin resistance by targeting SRPK1.

Main Methods:

  • Utilized breast cancer cell lines with varying cisplatin sensitivity.
  • Analyzed SRPK1 acetylation and phosphorylation levels following cisplatin treatment.
  • Assessed SRPK1 kinase activity and its impact on alternative splicing of anti-apoptotic genes.
  • Intervened by enhancing SRPK1 acetylation or inhibiting its kinase activity in resistant cells.

Main Results:

  • Cisplatin treatment induced SRPK1 acetylation in sensitive cells but reduced it in resistant cells.
  • In cisplatin-resistant cells, reduced SRPK1 acetylation correlated with increased phosphorylation and kinase activity.
  • This altered SRPK1 activity promoted splicing of anti-apoptotic variants, contributing to resistance.
  • Restoring SRPK1 acetylation or inhibiting its kinase activity re-sensitized resistant cells to cisplatin.

Conclusions:

  • Tip60-mediated SRPK1 acetylation is a critical determinant of cisplatin sensitivity in breast cancer.
  • Altered SRPK1 activity, driven by changes in acetylation and phosphorylation, plays a key role in acquired cisplatin resistance.
  • Targeting SRPK1 acetylation or kinase activity presents a promising therapeutic strategy to overcome chemotherapy resistance in breast cancer.

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