Transcriptomics

Dataset Information

296

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. 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Claudia Kerzendorfer   Markus K Müllner  Stefan Kubicek  Christoph Bock  Tiina Berg  Bernd Boidol  Marco P Licciardello  Robert Kralovics  Thomas Penz  Giulio Superti-Furga  Claudia Trefzer  Sebastian M Nijman  Gerhard Dürnberger  Jacques Colinge  Sara Sdelci  Michael Schuster 

PROVIDER: E-GEOD-61727 | ArrayExpress | 2014-11-21

SECONDARY ACCESSION(S): SRP047459GSE61727PRJNA261961

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications


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) a  ...[more]

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