Rb/e2f1 as a master regulator of cancer cell metabolism in advanced disease

Amy C. Mandigo, Wei Yuan, Kexin Xu, Peter Gallagher, Angel Pang, Yi Fang Guan, Ayesha A. Shafi, Chellappagounder Thangavel, Beshara Sheehan, Denisa Bogdan, Alec Paschalis, Jennifer J. McCann, Talya S. Laufer, Nicolas Gordon, Irina A. Vasilevskaya, Emanuela Dylgjeri, Saswati N. Chand, Matthew J. Schiewer, Josep Domingo-Domenech, Robert B. DenJeff Holst, Peter A. McCue, Johann S. de Bono, Christopher McNair, Karen E. Knudsen

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 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. Significance: This study identifies stage-specific consequences of RB loss across cancer progression that have a direct impact on tumor response to clinically utilized therapeutics. The study herein is the first to investigate the effect of RB loss on global metabolic regulation and link RB/E2F1 to redox control in multiple advanced diseases.

Original languageEnglish (US)
Pages (from-to)2334-2353
Number of pages20
JournalCancer Discovery
Volume11
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Oncology

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