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RB/E2F1 as a master regulator of cancer cell metabolism in advanced disease.

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Date
2021-04-20
ICR Author
De Bono, Johann
Author
Mandigo, AC
Yuan, W
Xu, K
Gallagher, P
Pang, A
Guan, YF
Shafi, AA
Thangavel, C
Sheehan, B
Bogdan, D
Paschalis, A
McCann, JJ
Laufer, TS
Gordon, N
Vasilevskaya, IA
Dylgjeri, E
Chand, SN
Schiewer, MJ
Domingo-Domenech, J
Den, RB
Holst, J
McCue, PA
de Bono, JS
McNair, C
Knudsen, KE
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Type
Journal Article
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Abstract
Loss of the retinoblastoma (RB) tumor suppressor protein is a critical step in reprogramming biological networks that drive cancer progression, although mechanistic insight has been largely limited to the impact of RB loss on cell cycle regulation. Here, isogenic modeling of RB loss identified disease stage-specific rewiring of E2F1 function, providing the first-in-field mapping of the E2F1 cistrome and transcriptome after RB loss across disease progression. Biochemical and functional assessment using both in vitro and in vivo models identified an unexpected, prominent role for E2F1 in regulation of redox metabolism after RB loss, driving an increase in the synthesis of the antioxidant, glutathione, specific to advanced disease. These E2F1-dependent events resulted in protection from reactive oxygen species (ROS) in response to therapeutic intervention. On balance, these findings reveal novel pathways through which RB loss promotes cancer progression and highlight potentially new nodes of intervention for treating RB-deficient cancers.
URI
https://repository.icr.ac.uk/handle/internal/4635
DOI
https://doi.org/10.1158/2159-8290.cd-20-1114
Collections
  • Clinical Studies
Research team
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2021-04-16
License start date
2021-04-20
Citation
Cancer discovery, 2021

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