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NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation

M P Licciardello1, M K Müllner1, G Dürnberger1

  • 1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Oncogene
|September 30, 2014
PubMed

Insights

Researchers discovered a link between NOTCH1 signaling and SUMOylation in breast cancer. Inhibiting SUMOylation harms NOTCH1-activated breast cancer cells, suggesting new therapeutic targets for this disease.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Breast cancer exhibits significant genetic heterogeneity.
  • Epigenetic alterations play a crucial role in breast cancer development.
  • Identifying synthetic lethalities with oncogenes can reveal therapeutic vulnerabilities.

Purpose of the Study:

  • To uncover novel synthetic lethal interactions in breast cancer by screening an epigenome-focused library.
  • To investigate the interplay between the NOTCH1 signaling pathway and the SUMOylation cascade in breast epithelial cells.

Main Methods:

  • Screening of an epigenome-focused short hairpin RNA library on engineered breast epithelial cell lines.
  • Targeted knockdown of UBC9 (UBE2I) and inhibition of the SAE1/UBA2 complex using ginkgolic acid.
  • Analysis of cell cycle progression and apoptosis induction in NOTCH1-activated cells upon SUMOylation inhibition.

Main Results:

  • Inhibition of the SUMOylation cascade (UBC9 knockdown or SAE1/UBA2 inhibition) impairs the growth of NOTCH1-activated breast epithelial cells.
  • NOTCH1 activation leads to depletion of unconjugated SUMO1 and SUMO2/3, increasing sensitivity to SUMOylation inhibition.
  • Sensitivity to SUMOylation inhibition in NOTCH1-activated cells correlates with unconjugated SUMO levels in patient-derived cell lines.

Conclusions:

  • A selective interaction exists between NOTCH1 signaling and the SUMOylation cascade in breast cancer.
  • Targeting the SUMOylation cascade represents a potential therapeutic strategy for NOTCH-driven breast cancers.
  • Further exploration of SUMOylation cascade inhibitors is warranted for treating specific breast cancer subtypes.

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