DSCAM-AS1-Driven Proliferation of Breast Cancer Cells Involves Regulation of Alternative Exon Splicing and 3′-End Usage

Abstract

DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B, and HER2-positive Breast Carcinoma (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). DSCAM-AS1 expression is analyzed in 30 public datasets and, additionally, by qRT-PCR in tumors from 93 BC patients, to uncover correlations with clinical data. Moreover, the effect of DSCAM-AS1 knockdown on gene expression and alternative splicing is studied by RNA-Seq in MCF-7 cells. We confirm DSCAM-AS1 overexpression in high grade Luminal A, B, and HER2+ BCs and find a significant correlation with disease relapse. In total, 908 genes are regulated by DSCAM-AS1-silencing, primarily involved in the cell cycle and inflammatory response. Noteworthily, the analysis of alternative splicing and isoform regulation reveals 2085 splicing events regulated by DSCAM-AS1, enriched in alternative polyadenylation sites, 3′UTR (untranslated region) shortening and exon skipping events. Finally, the DSCAM-AS1-interacting splicing factor heterogeneous nuclear ribonucleoprotein L (hnRNPL) is predicted as the most enriched RBP for exon skipping and 3′UTR events. The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer.

LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network

“…Higher expression of DSCAM-AS1 was significantly correlated with poor survival of ER + breast cancer patients. During the preparation of this manuscript, Elhasnaoui et al 65 reported a re-analysis of DSCAM-AS1 effect on survival in BRCA, resulted in a conclusion similar to ours. Intriguingly, in lung cancer, DSCAM-AS1 showed distinctive expression in LUAD but was almost undetectable in LUSC ( Figure S1 B).…”

Epigenetic Regulation of Alternative Splicing: How LncRNAs Tailor the Message

“…While mutations occurring from the 5′-end up to the middle of the LINC-HELLP are likely to cause loss of partner protein interactions, those at the far 3′-end increase their binding [ 120 ]. Among a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, DSCAM-AS1 has been recently found to be associated with tumor progression and tamoxifen resistance [ 121 ]. Researchers found over 2085 splicing events regulated by DSCAM-AS1 , including alternative polyadenylation sites, 3′ UTR shortening and exon skipping events.…”

“…Researchers found over 2085 splicing events regulated by DSCAM-AS1 , including alternative polyadenylation sites, 3′ UTR shortening and exon skipping events. DSCAM-AS1 affects target gene expression and causes changes in the AS by interacting with hnRNPL which appears to mediate the exon skipping and 3′ UTR usage by a mechanism not yet fully elucidated [ 121 ].…”

“…Interestingly, circRNAs have been also found associated with the splicing factor QKI during human EMT [123], and correlate with exon skipping throughout the genome in human endothelial cells [125]. and tamoxifen resistance [121]. Researchers found over 2085 splicing events regulated by DSCAM-AS1, including alternative polyadenylation sites, 3′ UTR shortening and exon skipping events.…”

Long Non-Coding RNA-Ribonucleoprotein Networks in the Post-Transcriptional Control of Gene Expression

“…By investigating the functions of DSCAM-AS1 (Down Syndrome Cell Adhesion Molecule antisense 1)—a lncRNA overexpressed in invasive breast cancers—De Bortoli and coworkers reported that the lncRNA, besides affecting global gene expression and producing changes in the AS of its targets, influences polyadenylation by regulating the alternative 3′ UTR usage of 360 genes [ 30 ]. These changes in the early steps of the post-transcriptional regulation of gene expression appear to depend on the interaction between DSCAM-AS1 and the nucleoplasm-enriched RBP hnRNPL [ 30 ].…”