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SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells.

ABSTRACT: Alternative splicing (AS) occurs in nearly all human genes and abnormal AS has a close association with cancer. Serine and arginine?rich splicing factor 6 (SRSF6), a canonical member of the serine/arginine?rich protein family, has been characterized as an important regulator of AS. However, the role of SRSF6 in regulating AS in cancers has remained to be fully elucidated. In the present study, the median expression of SRSF6 in tumors was determined to be higher compared with that in matched normal tissues in 13 out of 16 cancer types from The Cancer Genome Atlas. To investigate the biological effects of SRSF6 overexpression, an SRSF6?overexpression model of HeLa cells was constructed and it was revealed that SRSF6 overexpression resulted in significantly higher apoptosis and lower proliferation compared to control cells. Transcriptome analysis indicated that overexpression of SRSF6 in cancer cells induced large?scale changes in transcriptional expression levels and AS. Two groups of cervical cancer tumor samples in which SRSF6 was differentially expressed were then selected to analyze potential SRSF6?regulated AS. It was determined that the pattern of SRSF6?regulated AS in clinical samples was similar to that in cancer cells and AS genes were enriched in DNA damage response (DDR) pathways, including DNA repair and double?strand break repair via homologous recombination. Furthermore, AS events regulated by SRSF6 were validated using reverse transcription?quantitative PCR. The present results highlighted that SRSF6 is able to trigger the activation of DDR pathways via regulation of AS to influence cancer progression. These results markedly expand the current understanding of the mechanisms underlying SRSF6?mediated gene regulation and suggest the potential use of SRSF6 as a therapeutic target in cancer.

SUBMITTER: Yang X

PROVIDER: S-EPMC7551351 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells.

Yang Xiao X Zhan Peng P Feng Shuqiang S Ji He H Tian Wenjie W Wang Mengdi M Cheng Chao C Song Bin B

Oncology reports 20200903 5

Alternative splicing (AS) occurs in nearly all human genes and abnormal AS has a close association with cancer. Serine and arginine‑rich splicing factor 6 (SRSF6), a canonical member of the serine/arginine‑rich protein family, has been characterized as an important regulator of AS. However, the role of SRSF6 in regulating AS in cancers has remained to be fully elucidated. In the present study, the median expression of SRSF6 in tumors was determined to be higher compared with that in matched norm ...[more]

PMID: 32901876

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Project description:BackgroundAberrant spliced isoforms are specifically associated with cancer progression and metastasis. The cytoplasmic adaptor CRKL (v-crk avian sarcoma virus CT10 oncogene homolog-like) is a CRK like proto-oncogene, which encodes a SH2 and SH3 (src homology) domain-containing adaptor protein. CRKL is tightly linked to leukemia via its binding partners BCR-ABL and TEL-ABL, upregulated in multiple types of human cancers, and induce cancer cell proliferation and invasion. However, it remains unclear whether signaling adaptors such as CRKL could regulate alternative splicing.MethodsWe analyzed the expression level of CRKL in 305 cervical cancer tissue samples available in TCGA database, and then selected two groups of cancer samples with CRKL differentially expressed to analyzed potential CRKL-regulated alternative splicing events (ASEs). CRKL was knocked down by shRNA to further study CRKL-regulated alternative splicing and the activity of SR protein kinases in HeLa cells using RNA-Seq and Western blot techniques. We validated 43 CRKL-regulated ASEs detected by RNA-seq in HeLa cells, using RT-qPCR analysis of HeLa cell samples and using RNA-seq data of the two group of clinical cervical samples.ResultsThe expression of CRKL was mostly up-regulated in stage I cervical cancer samples. Knock-down of CRKL led to a reduced cell proliferation. CRKL-regulated alternative splicing of a large number of genes were enriched in cancer-related functional pathways, among which DNA repair and G2/M mitotic cell cycle, GnRH signaling were shared among the top 10 enriched GO terms and KEGG pathways by results from clinical samples and HeLa cell model. We showed that CRKL-regulated ASEs revealed by computational analysis using ABLas software in HeLa cell were highly validated by RT-qPCR, and also validated by cervical cancer clinical samples.ConclusionsThis is the first report of CRKL-regulation of the alternative splicing of a number of genes critical in tumorigenesis and cancer progression, which is consistent with CRKL reported role as a signaling adaptor and a kinase. Our results underline that the signaling adaptor CRKL might integrate the external and intrinsic cellular signals and coordinate the dynamic activation of cellular signaling pathways including alternative splicing regulation.

Dataset Information

SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells.

Publications

SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells.

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