Comprehensive landscape of epigenetic-dysregulated lncRNAs reveals a profound role of enhancers in carcinogenesis in BC subtypes

Molecular Therapy: Nucleic Acids

Fan Yang¹  Lei Yu²  Waidong Huang²  Haotian Xu²  Tengyue Li²  Zhijun Leng²  Hongying Zhao²  Junjie Lei²  Caiyu Zhang²  Shihua Lin²  Li Wang³  Jing Li⁴  Xiaoqin Liu⁵ 

[1] Corresponding author: Jing Li, Department of Ultrasonic Medicine, The 1st Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China.;College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China;Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China;Department of Ultrasonic Medicine, The 1st Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China;School of Life Sciences, Westlake University, Hangzhou 310024, China;

关键词: epigenetics;    long non-coding RNAs;    enhancer;    breast cancer subtypes;    prognostic biomarkers;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown