Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q
| Autor: | Radha L. Kalekar, Francisca Vazquez, Jesse S. Boehm, Thomas A. Skipper, Andrew J. Aguirre, Andrew L. Hong, Chen Yuan, Todd R. Golub, Guillaume Kugener, Westley W. Wu, Kimberly Stegmaier, Adam D. Durbin, Nancy Dumont, Michael V. Rothberg, Jasper E. Neggers, David E. Root, Neekesh V. Dharia, Mai Abdusamad, Andrew D. Cherniack, Adhana Asfaw, Brian M. Wolpin, Jeremie Kalfon, Liam F. Spurr, Brenton R. Paolella, Alfredo Gonzalez, William C. Hahn, Aviad Tsherniak, John M. Krill-Burger, Federica Piccioni, Annan Yang, Yvonne Y. Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Vacuolar Proton-Translocating ATPases QH301-705.5 16q loss Synthetic lethality Biology General Biochemistry Genetics and Molecular Biology ESCRT Article law.invention CDH1 03 medical and health sciences 0302 clinical medicine 18q loss law Cell Line Tumor Neoplasms medicine Humans cancer Biology (General) Gene lcsh:QH301-705.5 Endosomal Sorting Complexes Required for Transport Cancer medicine.disease synthetic lethality VPS4B 030104 developmental biology VPS4A lcsh:Biology (General) Cancer research biology.protein Suppressor ATPases Associated with Diverse Cellular Activities Functional genomics 030217 neurology & neurosurgery Cytokinesis |
| Zdroj: | Cell Reports, Vol 33, Iss 11, Pp 108493-(2020) Cell reports Cell Reports, Vol 36, Iss 2, Pp 109367-(2021) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY Few therapies target the loss of tumor suppressor genes in cancer. We examine CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new therapeutic targets associated with genomic loss of tumor suppressor genes. The endosomal sorting complexes required for transport (ESCRT) ATPases VPS4A and VPS4B score as strong synthetic lethal dependencies. VPS4A is essential in cancers harboring loss of VPS4B adjacent to SMAD4 on chromosome 18q and VPS4B is required in tumors with co-deletion of VPS4A and CDH1 (E-cadherin) on chromosome 16q. We demonstrate that more than 30% of cancers selectively require VPS4A or VPS4B. VPS4A suppression in VPS4B-deficient cells selectively leads to ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, apoptosis, and potent tumor regression. CRISPR-SpCas9 screening and integrative genomic analysis reveal other ESCRT members, regulators of abscission, and interferon signaling as modifiers of VPS4A dependency. We describe a compendium of synthetic lethal vulnerabilities and nominate VPS4A and VPS4B as high-priority therapeutic targets for cancers with 18q or 16q loss. In Brief Neggers, Paolella, and colleagues identify the ATPases VPS4A and VPS4B as selective vulnerabilities and potential therapeutic targets in cancers harboring loss of chromosome 18q or 16q. In VPS4B-deficient cancers, VPS4A suppression leads to ESCRT-III dysfunction, nuclear deformation, and abscission defects. Moreover, ESCRT proteins and interferons can modulate dependency on VPS4A. Graphical Abstract |
| Databáze: | OpenAIRE |
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