NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation

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.
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https://hal.umontpellier.fr/hal-02287227
Contributeur : Mélanie Karli <>
Soumis le : vendredi 13 septembre 2019 - 16:44:42
Dernière modification le : samedi 14 septembre 2019 - 01:27:01

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M Licciardello, M Müllner, G Dürnberger, C Kerzendorfer, B Boidol, et al.. NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. Oncogene, Nature Publishing Group, 2015, 34 (29), pp.3780-3790. ⟨10.1038/onc.2014.319⟩. ⟨hal-02287227⟩

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