| Added by | mollevi |
|---|---|
| Last modified by | jacques.colinge |
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation |
| Creator | Licciardello et al. |
| Author | M. P. Licciardello |
| Author | M. K. Mullner |
| Author | G. Durnberger |
| Author | C. Kerzendorfer |
| Author | B. Boidol |
| Author | C. Trefzer |
| Author | S. Sdelci |
| Author | T. Berg |
| Author | T. Penz |
| Author | M. Schuster |
| Author | C. Bock |
| Author | R. Kralovics |
| Author | G. Superti-Furga |
| Author | J. Colinge |
| Author | S. M. Nijman |
| Author | S. Kubicek |
| 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 | Oncogene |
| Volume | 34 |
| Pages | 3780-90 |
| Date | Jul 2015 |
| Journal Abbr | Oncogene |
| DOI | 10.1038/onc.2014.319 |
| ISSN | 1476-5594 (Electronic) 0950-9232 (Linking) |
| Tags | *Gene Expression Regulation, Neoplastic, *Transcriptional Activation, Apoptosis/drug effects/genetics, Blotting, Western, Breast Neoplasms/genetics/metabolism/pathology, Cell Cycle/drug effects/genetics, Cell Line, Cell Line, Tumor, Cell Proliferation/drug effects/genetics, Coculture Techniques, Flow Cytometry, Humans, Microscopy, Fluorescence, original, Receptor, Notch1/*genetics/metabolism, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Salicylates/pharmacology, Signal Transduction/drug effects/*genetics, Small Ubiquitin-Related Modifier Proteins/genetics/metabolism, SUMO-1 Protein/genetics/metabolism, Sumoylation/drug effects/genetics, Ubiquitin-Activating Enzymes/genetics/metabolism, Ubiquitin-Conjugating Enzymes/genetics/metabolism, Ubiquitins/genetics/metabolism |
| Date Added | 2018/11/14 - 11:48:35 |
| Date Modified | 2019/05/14 - 20:59:11 |
| Notes and Attachments | (Note) (Note) 25263445 (Attachment) |
Institut de Recherche en Cancérologie de
