Differential impact of RB status on E2F1 reprogramming in human cancer

Christopher McNair, Kexin Xu, Amy C. Mandigo, Matteo Benelli, Benjamin Leiby, Daniel Rodrigues, Johan Lindberg, Henrik Gronberg, Mateus Crespo, Bram De Laere, Luc Dirix, Tapio Visakorpi, Fugen Li, Felix Y. Feng, Johann De Bono, Francesca Demichelis, Mark A. Rubin, Myles Brown, Karen E. Knudsen

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)341-358
Number of pages18
JournalJournal of Clinical Investigation
Volume128
Issue number1
DOIs
StatePublished - Jan 2 2018

ASJC Scopus subject areas

  • Medicine(all)

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    McNair, C., Xu, K., Mandigo, A. C., Benelli, M., Leiby, B., Rodrigues, D., Lindberg, J., Gronberg, H., Crespo, M., De Laere, B., Dirix, L., Visakorpi, T., Li, F., Feng, F. Y., De Bono, J., Demichelis, F., Rubin, M. A., Brown, M., & Knudsen, K. E. (2018). Differential impact of RB status on E2F1 reprogramming in human cancer. Journal of Clinical Investigation, 128(1), 341-358. https://doi.org/10.1172/JCI93566