SCIRT lncRNA restrains tumorigenesis by opposing transcriptional programs of tumor-initiating cells.
Author(s)
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.
Date Issued
2021-02
Date Acceptance
2020-11-05
Citation
Cancer Research, 2021, 81 (3), pp.580-593
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
Action Against Cancer
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33172932
PII: 0008-5472.CAN-20-2612
Grant Number
022016-01
NIHR-RP-011-053
RDB01 79560
Subjects
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-11-10