Widespread Alternative Splicing Changes in Metastatic Breast Cancer Cells

• Main Authors: Jagyeong Oh, Davide Pradella, Changwei Shao, Hairi Li, Namjeong Choi, Jiyeon Ha, Sonia Ruggiero, Xiang-Dong Fu, Xuexiu Zheng, Claudia Ghigna, Haihong Shen
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Cells
• Subjects: alternative splicing; breast cancer; exon skipping; cancer metastasis; <i>DCUN1D5</i>
• Online Access: https://www.mdpi.com/2073-4409/10/4/858

Aberrant alternative splicing (AS) is a hallmark of cancer and a potential target for novel anti-cancer therapeutics. Breast cancer-associated AS events are known to be linked to disease progression, metastasis, and survival of breast cancer patients. To identify altered AS programs occurring in metastatic breast cancer, we perform a global analysis of AS events by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq). We demonstrate that, relative to low-metastatic, high-metastatic breast cancer cells show different AS choices in genes related to cancer progression. Supporting a global reshape of cancer-related splicing profiles in metastatic breast cancer we found an enrichment of RNA-binding motifs recognized by several splicing regulators, which have aberrant expression levels or activity during breast cancer progression, including SRSF1. Among SRSF1-regulated targets we found <i>DCUN1D5</i>, a gene for which skipping of exon 4 in its pre-mRNA introduces a premature termination codon (PTC), thus generating an unstable transcript degraded by nonsense-mediated mRNA decay (NMD). Significantly, distinct breast cancer subtypes show different <i>DCUN1D5</i> isoform ratios with metastatic breast cancer expressing the highest level of the NMD-insensitive <i>DCUN1D5</i> mRNA, thus showing high <i>DCUN1D5</i> expression levels, which are ultimately associated with poor overall and relapse-free survival in breast cancer patients. Collectively, our results reveal global AS features of metastatic breast tumors, which open new possibilities for the treatment of these aggressive tumor types.