SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells
| Autor: | Justin Stebbing, Tracy Nissan, Angela Yiu, Aleksandra Dabrowska, Leandro Castellano, Keith W. Vance, Sladjana Zagorac, Nuria Casas-Vila, Alex de Giorgio, Ylenia Lombardo, Paul Cathcart, Igor Ulitsky, Silvia Ottaviani, Mark Kalisz, Neta Degani, Alistair Tweedie |
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| Přispěvatelé: | Action Against Cancer, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Breast Neoplasms macromolecular substances Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Cell Line Tumor Gene expression Transcriptional regulation medicine Humans 1112 Oncology and Carcinogenesis Oncology & Carcinogenesis Promoter Cell cycle Cell Cycle Gene Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell FOXM1 RNA Long Noncoding |
| Zdroj: | 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 & Castellano, L 2021, ' SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells ', Cancer Research, vol. 81, no. 3, pp. 580-593 . https://doi.org/10.1158/0008-5472.CAN-20-2612 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. See related commentary by Pardini and Dragomir, p. 535 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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