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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2014
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| _version_ | 1797064342234988544 |
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| author | Licciardello, M Müllner, M Dürnberger, G Kerzendorfer, C Boidol, B Trefzer, C Sdelci, S Berg, T Penz, T Schuster, M Bock, C Kralovics, R Superti-Furga, G Colinge, J Nijman, S Kubicek, S |
| author_facet | Licciardello, M Müllner, M Dürnberger, G Kerzendorfer, C Boidol, B Trefzer, C Sdelci, S Berg, T Penz, T Schuster, M Bock, C Kralovics, R Superti-Furga, G Colinge, J Nijman, S Kubicek, S |
| author_sort | Licciardello, M |
| collection | OXFORD |
| description | 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.Oncogene advance online publication, 29 September 2014; doi:10.1038/onc.2014.319. |
| first_indexed | 2024-03-06T21:12:54Z |
| format | Journal article |
| id | oxford-uuid:3ec87bde-1a65-465a-88cb-32baaf76e916 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:12:54Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:3ec87bde-1a65-465a-88cb-32baaf76e9162022-03-26T14:27:44ZNOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3ec87bde-1a65-465a-88cb-32baaf76e916EnglishSymplectic Elements at Oxford2014Licciardello, MMüllner, MDürnberger, GKerzendorfer, CBoidol, BTrefzer, CSdelci, SBerg, TPenz, TSchuster, MBock, CKralovics, RSuperti-Furga, GColinge, JNijman, SKubicek, SBreast 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.Oncogene advance online publication, 29 September 2014; doi:10.1038/onc.2014.319. |
| spellingShingle | Licciardello, M Müllner, M Dürnberger, G Kerzendorfer, C Boidol, B Trefzer, C Sdelci, S Berg, T Penz, T Schuster, M Bock, C Kralovics, R Superti-Furga, G Colinge, J Nijman, S Kubicek, S NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title_full | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title_fullStr | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title_full_unstemmed | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title_short | NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation. |
| title_sort | notch1 activation in breast cancer confers sensitivity to inhibition of sumoylation |
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