NOTCH1 Activation in Breast Cancer Confers Sensitivity to Inhibition of SUMOylation

Oncogene. 2015 Jul;34(29):3780-90. doi: 10.1038/onc.2014.319. Epub 2014 Sep 29.

Abstract

Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Coculture Techniques
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Microscopy, Fluorescence
  • RNA Interference
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism
  • Salicylates / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation / drug effects
  • Sumoylation / genetics
  • Transcriptional Activation*
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / metabolism

Substances

  • NOTCH1 protein, human
  • Receptor, Notch1
  • SUMO-1 Protein
  • SUMO1 protein, human
  • SUMO2 protein, human
  • SUMO3 protein, human
  • Salicylates
  • Small Ubiquitin-Related Modifier Proteins
  • UBA2 protein, human
  • Ubiquitins
  • ginkgolic acid
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Activating Enzymes
  • ubiquitin-conjugating enzyme UBC9