TY - JOUR
T1 - Rb/e2f1 as a master regulator of cancer cell metabolism in advanced disease
AU - Mandigo, Amy C.
AU - Yuan, Wei
AU - Xu, Kexin
AU - Gallagher, Peter
AU - Pang, Angel
AU - Guan, Yi Fang
AU - Shafi, Ayesha A.
AU - Thangavel, Chellappagounder
AU - Sheehan, Beshara
AU - Bogdan, Denisa
AU - Paschalis, Alec
AU - McCann, Jennifer J.
AU - Laufer, Talya S.
AU - Gordon, Nicolas
AU - Vasilevskaya, Irina A.
AU - Dylgjeri, Emanuela
AU - Chand, Saswati N.
AU - Schiewer, Matthew J.
AU - Domingo-Domenech, Josep
AU - Den, Robert B.
AU - Holst, Jeff
AU - McCue, Peter A.
AU - de Bono, Johann S.
AU - McNair, Christopher
AU - Knudsen, Karen E.
N1 - Funding Information:
This work was supported by NIH T32 grant (GM100836; to A.C. Mandigo); NIH R01 grants (5R01CA17640105, 5R01CA18256905, 5R01CA21732903; to K.E. Knudsen); NCI F99 grant (F99CA212225; to J. McCann); and the Sidney Kimmel Cancer Center (SKCC) Support Grant (5P30CA056036). Additional support was provided by the SKCC Cancer Genomics, Translational Research/Pathology and Biostatistics core services, specifically Dr. Benjamin Leiby. We would like to thank Dr. Jun Lou (John Hopkins University, Baltimore, MD) for providing the LNCaP95 cells utilized in this study. The sponsors were critical in study design, data collection, analysis, interpretation, and review of the manuscript.
Funding Information:
GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, and Taiho, and grants, personal fees, and other support from Vertex Pharmaceuticals outside the submitted work; in addition, J.S. de Bono has a patent for DNA damage repair inhibitors for treatment of cancer (patent no. WO 2005 053662 - no personal income) issued and licensed to AstraZeneca and a patent for 17-substituted steroids useful in cancer treatment (patent no. US5604213 - no personal income) issued and licensed to Janssen. K.E. Knudsen reports grants from NCI during the conduct of the study; other support from Janssen and Genentech, and other support from CellCentric outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85109351814&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-1114
DO - 10.1158/2159-8290.CD-20-1114
M3 - Article
C2 - 33879449
AN - SCOPUS:85109351814
SN - 2159-8274
VL - 11
SP - 2334
EP - 2353
JO - Cancer Discovery
JF - Cancer Discovery
IS - 9
ER -