1. Comprehensive landscape of epigenetic-dysregulated lncRNAs reveals a profound role of enhancers in carcinogenesis in BC subtypes
- Author
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Waidong Huang, Hongying Zhao, Tengyue Li, Li Wang, Xiaoqin Liu, Haotian Xu, Caiyu Zhang, Fan Yang, Lei Yu, Junjie Lei, Jing Li, Zhijun Leng, and Shihua Lin
- Subjects
0301 basic medicine ,Cellular differentiation ,medicine.disease_cause ,prognostic biomarkers ,03 medical and health sciences ,long non-coding RNAs ,0302 clinical medicine ,Drug Discovery ,medicine ,Epigenetics ,EP300 ,biology ,epigenetics ,lcsh:RM1-950 ,Cancer ,medicine.disease ,Bromodomain ,breast cancer subtypes ,030104 developmental biology ,Histone ,lcsh:Therapeutics. Pharmacology ,030220 oncology & carcinogenesis ,DNA methylation ,biology.protein ,Cancer research ,Molecular Medicine ,Original Article ,enhancer ,Carcinogenesis - Abstract
Aberrant expression of long non-coding RNAs (lncRNA) is associated with altered DNA methylation and histone modifications during carcinogenesis. However, identifying epigenetically dysregulated lncRNAs and characterizing their functional mechanisms in different cancer subtypes are still major challenges for cancer studies. In this study, we systematically analyzed the epigenetic alterations of lncRNAs at important regulatory elements in three breast cancer subtypes. We identified 87, 691, and 1,197 epigenetically dysregulated lncRNAs in luminal, basal, and claudin-low subtypes of breast cancer, respectively. The landscape of epigenetically dysregulated lncRNAs at enhancer elements revealed that epigenetic changes of the majority of lncRNAs occurred in a subtype-specific manner and contributed to subtype-specific biological functions. We identified six acetylation of lysine 27 on histone H3 (H3K27ac)-dysregulated lncRNAs and three DNA methylation-dysregulated lncRNAs (CTC-303L1.2, RP11-738B7.1, and SLC26A4-AS1) as prognostic biomarkers of basal subtype. These lncRNAs were involved in immune response-related biological functions. Treatment of the basal breast cancer cell line MDA-MB-468 with CREBBP/EP300 bromodomain inhibitors downregulated H3K27 acetylation levels and caused a decrease in the expression of five H3K27ac-dysregulated lncRNAs (LINC00393, KB-1836B5.1, RP1-140K8.5, AC005162.1, and AC020916.2) and inhibition of the growth of breast cancer cells. One epigenetically dysregulated lncRNA (LINC01983) and four lncRNA regulators (UCA1, RP11-221J22.2, RP11-221J22.1, and RP1-212P9.3) were identified as prognostic biomarkers of the luminal molecular subtype of breast cancer by controlling the tumor necrosis factor (TNF) signaling pathway, T helper (Th)17 cell differentiation, and T cell migration. Finally, our results highlighted a profound role of enhancer-related H3K27ac-dysregulated lncRNAs, DNA methylation-dysregulated lncRNAs, and lncRNA regulators in breast cancer subtype carcinogenesis and their potential prognostic value., Graphical Abstract, The corresponding authors and colleagues identified H3K27ac-dysregulated lncRNAs (LINC00393, KB-1836B5.1, RP1-140K8.5, AC005162.1, and AC020916.2) and DNA methylation-dysregulated lncRNAs (CTC-303L1.2, RP11-738B7.1, and SLC26A4-AS1) as prognostic biomarkers of basal subtypes. LINC01983, UCA1, RP11-221J22.2, RP11-221J22.1, and RP1-212P9.3 act as prognostic biomarkers of the luminal subtype. The inhibition of enhancer-related lncRNAs could suppress breast cancer cell growth.
- Published
- 2021