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

Title: SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells.
Authors: 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, KW
Ulitsky, I
Stebbing, J
Castellano, L
Item Type: Journal Article
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 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.
Issue Date: Feb-2021
Date of Acceptance: 5-Nov-2020
URI: http://hdl.handle.net/10044/1/84149
DOI: 10.1158/0008-5472.CAN-20-2612
ISSN: 0008-5472
Publisher: American Association for Cancer Research
Start Page: 580
End Page: 593
Journal / Book Title: Cancer Research
Volume: 81
Issue: 3
Copyright Statement: ©2020, American Association for Cancer Research.
Sponsor/Funder: Action Against Cancer
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 022016-01
NIHR-RP-011-053
RDB01 79560
Keywords: 1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Conference Place: United States
Online Publication Date: 2020-11-10
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine