Journal
CELL REPORTS
Volume 31, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.03.029
Keywords
-
Categories
Funding
- European Research Council (ERC)
- European Union [336045]
- German Network for Bioinformatics Infrastructure [031A537B]
- Alexander S. Onassis Public Benefit Foundation, Greece [F ZL 084-1/2015-2016]
Ask authors/readers for more resources
TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressors enhances cellular proliferation and transformation. Loss of neddylation pathway genes promotes uncontrolled proliferation exclusively in TP53-deficient cells. Combined loss of CUL3 and TP53 activates an oncogenic transcriptional program governed by the nuclear factor kappa B (NF-kappa B), AP-1, and transforming growth factor beta (TGF-beta) pathways. This program maintains persistent cellular proliferation, induces partial epithelial to mesenchymal transition, and increases DNA damage, genomic instability, and chromosomal rearrangements. Our findings reveal CUL3 loss as a key event stimulating persistent proliferation in TP53-deficient cells. These findings may be clinically relevant, since TP53-CUL3-deficient cells are highly sensitive to ataxia telangiectasia mutated (ATM) inhibition, exposing a vulnerability that could be exploited for cancer treatment.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available