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

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posted on 2023-06-09, 22:10 authored by 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 CastellanoLeandro Castellano
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 and increase in self-renewal gene expression is coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long non-coding RNA (lncRNA) that we name 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 towards repression. These data suggest that the interaction of a lncRNA with EZH2 can alter the affinity of EZH2 for its protein binding partners to regulate cancer cell state transitions.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Cancer Research

ISSN

0008-5472

Publisher

American Association for Cancer Research

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-11-12

First Open Access (FOA) Date

2021-11-11

First Compliant Deposit (FCD) Date

2020-11-12

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    University of Sussex (Publications)

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