GSE61727
NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation
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. Overall design: We treated MCF10A and NOTCH1 cells with either DMSO or ginkgolic acid 30 uM for 3 days. Two replicates have been analysed for each condition.