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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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Acknowledgements

We thank John Doench, Serena Silver and David E Root (Broad Institute of MIT and Harvard) for shRNA tools and screening protocols; Johannes Bigenzahn (CeMM) for providing the pMSCV-StrepHA-GW-hPGK-Bla vector; and Erika Schirghuber (CeMM) and Berend Snijder (CeMM) for critically reading the manuscript. SK acknowledges support by a Marie Curie Career Integration Grant, the Austrian Federal Ministry of Science, Research and Economy and the National Foundation for Research, Technology and Development.

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Correspondence to S Kubicek.

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Licciardello, M., Müllner, M., Dürnberger, G. et al. NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. Oncogene 34, 3780–3790 (2015). https://doi.org/10.1038/onc.2014.319

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