| Literature DB >> 26673326 |
Chad M Toledo1, Yu Ding2, Pia Hoellerbauer1, Ryan J Davis3, Ryan Basom4, Emily J Girard5, Eunjee Lee6, Philip Corrin2, Traver Hart7, Hamid Bolouri2, Jerry Davison4, Qing Zhang4, Justin Hardcastle2, Bruce J Aronow8, Christopher L Plaisier9, Nitin S Baliga9, Jason Moffat7, Qi Lin10, Xiao-Nan Li10, Do-Hyun Nam11, Jeongwu Lee12, Steven M Pollard13, Jun Zhu6, Jeffery J Delrow4, Bruce E Clurman14, James M Olson15, Patrick J Paddison16.
Abstract
To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, most likely as a result of oncogenic signaling, causing GBM-specific lethality.Entities:
Keywords: CRISPR-Cas9; Glioblastoma; Myt1; PKMYT1; WEE1; cancer therapeutics; functional genomics; gene editing
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Year: 2015 PMID： 26673326 PMCID： PMC4691575 DOI： 10.1016/j.celrep.2015.11.021
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423