Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

• Published in: RNA (Cambridge) Vol. 20; no. 10; pp. 1621 - 1631
• Main Authors: Lin, Jung-Chun, Lin, Ching-Yu, Tarn, Woan-Yuh, Li, Fang-Yu
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2014
• Subjects: Apoptosis; Blotting, Western; Breast - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; Cell Proliferation; Cells, Cultured; Electrophoretic Mobility Shift Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA Splicing - genetics; RNA, Messenger - genetics; RNA, Small Interfering - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Transcriptional Activation; breast cancer; alternative splicing; RNA binding motif protein 4; MCL-1
• ISSN: 1355-8382; 1469-9001; 1469-9001
• DOI: 10.1261/rna.045583.114

Imbalanced splicing of premessenger RNA is typical of tumorous malignancies, and the regulatory mechanisms involved in several tumorigenesis-associated splicing events are identified. Elevated expression of serine-arginine protein kinase 1 (SRPK1) may participate in the pathway responsible for the dysregulation of splicing events in malignant tumor cells. In this study, we observed a correlation between the cytoplasmic accumulation of RNA-binding motif protein 4 (RBM4) and up-regulated SRPK1 in breast cancer cells. The production of the IR-B and MCL-1 S transcripts was induced separately by the overexpression of RBM4 and SRPK1 gene silencing. Overexpressed RBM4 simultaneously bound to the CU-rich elements within the MCL-1 exon2 and the downstream intron, which subsequently facilitated the exclusion of the regulated exon. Breast cancer cells are deprived of apoptotic resistance through the RBM4-mediated up-regulation of the IR-B and MCL-1 S transcripts. These findings suggest that the splicing events regulated by the SRPK1-RMB4 network may contribute to tumorigenesis through altered sensitivity to apoptotic signals in breast cancer cells.