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

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.

Epigenetic-dysregulated lncRNAs in Prostate Cancer Based on Multi-omics Analysis

“…2). Based on the multiple relationships between epi-lncRNAs and PCGs (inter-gene, overlap, partial overlap, intron or exon) [23,24], the more complex the splicing pattern of lncRNA is, the more likely it is to be regulated by abnormal epigenetic modi cation [25]. Our results also coincide with the above view.…”

Identification and Roles of miR-29b-1-3p and miR29a-3p-Regulated and Non-Regulated lncRNAs in Endocrine-Sensitive and Resistant Breast Cancer Cells

“…UCA1 expression was associated with LN metastasis in breast tumors and reduced OS in BC patients [ 138 ]. On the other hand, a recent review found that reduced UCA1 was a poor prognostic biomarker of luminal BC by controlling the tumor necrosis factor (TNF) signaling and immune responses [ 139 ]. UCA1 transcription is directly upregulated by TGFβ-activated TEAD1 (TEA domain transcription factor 1) and by SMAD2/3 recruitment to the UCA1 promoter in BC cells [ 140 ].…”

DNA Based and Stimuli-Responsive Smart Nanocarrier for Diagnosis and Treatment of Cancer: Applications and Challenges

“…Therefore, it gives an attractive option for triggering specific cancer targeting. The differences in reduction efficiency between tumor and normal tissues between extracellular and intracellular environments can be useful for targeted release at the malignant site [ 143 , 144 ]. The GSH concentration is very low in the extracellular environment but is concentrated within the cell inside the cytosol.…”