Differential impact of RB status on E2F1 reprogramming in human cancer.

McNair, Christopher; Xu, Kexin; Mandigo, Amy C; Benelli, Matteo; Leiby, Benjamin; Rodrigues, Daniel; Lindberg, Johan; Gronberg, Henrik; Crespo, Mateus; De Laere, Bram; Dirix, Luc; Visakorpi, Tapio; Li, Fugen; Feng, Felix Y; de Bono, Johann; Demichelis, Francesca; Rubin, Mark Andrew; Brown, Myles; Knudsen, Karen E (2018). Differential impact of RB status on E2F1 reprogramming in human cancer. Journal of clinical investigation, 128(1), pp. 341-358. American Society for Clinical Investigation 10.1172/JCI93566

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The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects distinct from cell cycle control. Mechanistically, RB loss led to E2F1 cistrome expansion and different binding specificity, alterations distinct from those observed after functional RB inactivation. Additionally, identification of protumorigenic transcriptional networks specific to RB loss that were validated in clinical samples demonstrated the ability of RB loss to differentially reprogram E2F1 in human cancers. Together, these findings not only identify tumor-suppressive functions of RB that are distinct from cell cycle control, but also demonstrate that the molecular consequence of RB loss is distinct from RB inactivation. Thus, these studies provide insight into how RB loss promotes disease progression, and identify new nodes for therapeutic intervention.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

500 Science
500 Science > 570 Life sciences; biology

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

12 Feb 2018 08:42

Last Modified:

23 Oct 2019 13:43

Publisher DOI:

10.1172/JCI93566

PubMed ID:

29202480

Uncontrolled Keywords:

Cell Biology Cell cycle Oncology Prostate cancer Transcription

BORIS DOI:

10.7892/boris.110724

URI:

https://boris.unibe.ch/id/eprint/110724

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