Inhibition of Pluripotency Networks by the Rb Tumor Suppressor Restricts Reprogramming and Tumorigenesis

Abstract

SUMMARY Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.

A basal stem cell signature identifies aggressive prostate cancer phenotypes

“…These genes are vital for maintaining self-renewal capacity in embryonic and adult stem cells (66). Recent evidence has also shown Rb alterations can facilitate reprogramming of fibroblasts to a pluripotent state through derepression of pluripotency factors such as SOX2 (67). In the CD49f Hi population, we found enrichment of both E2F and SOX2 targets, further supporting that these networks may be part of a stem-like component common to small cell carcinomas.…”

Tissue-specific targeting of cell fate regulatory genes by E2f factors

“…8 Another recent study demonstrated that pRb inhibits the ability of murine fibroblasts to reprogram to a pluripotent state by inhibiting E2f transcriptional activity, and that this process is also unaccompanied by changes in cell cycle dynamics. 44 Thus it appears that, at least in cells that are actively making stem cell fate decisions, pRb/E2f factors can direct these decisions independently from cell cycle regulation. Our data suggest that this is through direct regulation of networks of cell fate-associated genes.…”

RB1: a prototype tumor suppressor and an enigma

“…Recent work has suggested that Notch signaling may be important in mouse models of small-cell lung cancer, one of the most common types of RB1 mutant cancers (George et al 2015). Inactivation of Sox2 has also been shown to suppress RB1 mutant pituitary tumors in mouse models (Kareta et al 2015). In part, these effects may reflect the context-specific signals that are important for the formation of tumor-initiating cells, signals that likely vary between cancer types.…”

“…Currently, there is surprisingly little information about precisely which genomic loci are controlled directly and specifically by pRB. The genomic distribution of pRB varies between cycling, quiescent, and senescent cells (Wells et al 2003;Chicas et al 2010;Ferrari et al 2014;Kareta et al 2015). It is uncertain what proportion of pRB is bound directly at E2F-regulated promoters or whether this is the most functionally relevant population of the protein, and it is unclear which or how many E2F-regulated promoters are truly rate-limiting for pRB-mediated control of cell proliferation.…”