SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells

Zagorac, S., de Giorgio, A., Dabrowska, A., Kalisz, M., Casas-Vila, N., Cathcart, P., Yiu, A., Ottaviani, S. ORCID: 0000-0002-8830-9947, Degani, N., Lombardo, Y., Tweedie, A., Nissan, T., Vance, K.W., Ulitsky, I., Stebbing, J. and Castellano, L., 2021. SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells. Cancer Research, 81 (3), pp. 580-593. ISSN 0008-5472

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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.

Item Type: Journal article
Publication Title: Cancer Research
Creators: Zagorac, S., de Giorgio, A., Dabrowska, A., Kalisz, M., Casas-Vila, N., Cathcart, P., Yiu, A., Ottaviani, S., Degani, N., Lombardo, Y., Tweedie, A., Nissan, T., Vance, K.W., Ulitsky, I., Stebbing, J. and Castellano, L.
Publisher: American Association for Cancer Research
Date: 1 February 2021
Volume: 81
Number: 3
ISSN: 0008-5472
Identifiers:
NumberType
10.1158/0008-5472.CAN-20-2612DOI
1537659Other
Divisions: Schools > School of Science and Technology
Record created by: Laura Ward
Date Added: 20 Apr 2022 15:35
Last Modified: 20 Apr 2022 15:36
URI: http://irep.ntu.ac.uk/id/eprint/46147

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