SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells

Sladjana Zagorac, Alex de Giorgio, Aleksandra Dabrowska, Mark Kalisz, Nuria Casas-Vila, Paul Cathcart, Angela Yiu, Silvia Ottaviani, Neta Degani, Ylenia Lombardo, Alistair Tweedie, Tracy Nissan, Keith W. Vance, Igor Ulitsky, Justin Stebbing, Leandro Castellano

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Abstract

In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. Significance: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.

Original languageEnglish
Pages (from-to)580-593
Number of pages14
JournalCancer Research
Volume81
Issue number3
Early online date10 Nov 2020
DOIs
Publication statusPublished - 1 Feb 2021

Bibliographical note

Funding Information:
P. Cathcart reports grants from Medical Research Council (MRC) during the conduct of the study. S. Ottaviani reports grants from Action Against Cancer during the conduct of the study. J. Stebbing conflicts can be found at: https://www.nature. com/onc/editors, none of which are relevant here. L. Castellano reports grants from Action Against Cancer during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
The authors thank Action Against Cancer (grant numbers: P75997_WSCC and PF9671), the Searle Memorial Trust, Charles and Diane Herlinger, Alessandro Dusi, Julian and Cat O’ Dell, Sofiya Machulskaya, and Jackie McCarthy for funding this study. This work used the computing resources of the UK MEDical BIOinformatics partnership—aggregation, integration, visualization, and analysis of large, complex data (UK MED-BIO)—which is supported by the Medical Research Council. This study was supported by the Sussex University and the Imperial BRC and ECMC.

Publisher Copyright:
©2020 American Association for Cancer Research.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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