A genome landscape of SRSF3-regulated splicing events and gene expression in human osteosarcoma U2OS cells

Ajiro, Masahiko; Jia, Rong; Yang, Yanqin; Zhu, Jun; Zheng, Zhi-Ming

doi:10.1093/nar/gkv1500

Cited by 103 publications

(124 citation statements)

References 110 publications

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“…We searched the targets of SRSF3 in our previous splice array data (NCBI GEO accession no. GSE22149), in which osteosarcoma U2OS cells were treated with anti-SRSF3 or non-specific (NS) siRNA26. In the present study, we found that the expression level of hnRNP L decreased upon SRSF3 knockdown in U2OS cells (fold change: −1.98, p = 0.00516).…”

Section: Resultssupporting

confidence: 50%

HnRNP L is important for the expression of oncogene SRSF3 and oncogenic potential of oral squamous cell carcinoma cells

Jia

Zhang

Liu

et al. 2016

Sci Rep

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Oral squamous cell carcinoma (OSCC) is the leading cause of death related to oral diseases. The mechanisms of OSCC development remain largely unknown. Heterogeneous nuclear ribonucleoprotein L (HnRNP L) is a multi-functional splicing factor. It has been reported to be an important regulator of apoptosis. However, the functions of hnRNP L in cancer need to be further explored. In the present study, we found that OSCC tissues expressed significantly higher levels of hnRNP L than normal tissues. Depletion of hnRNP L retarded cell growth, cell migration, and tumorigenesis of OSCC cells. HnRNP L regulates both the expression of oncogenic splicing factor SRSF3 and the alternative splicing of SRSF3 exon 4. Expression of hnRNP L is correlated with SRSF3 expression in OSCC tissues. These findings suggest that hnRNP L is important for the pathogenesis of OSCC and may be a novel potential therapeutic target of OSCC.

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Section: Resultssupporting

confidence: 50%

HnRNP L is important for the expression of oncogene SRSF3 and oncogenic potential of oral squamous cell carcinoma cells

Jia

Zhang

Liu

et al. 2016

Sci Rep

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“…In addition to its regulation of viral gene expression, SRSF3 has been characterized as an oncogenic factor (66)(67)(68), and it effects global change of the gene expression of hundreds of mammalian genes to maintain cell homeostasis (34,39,(69)(70)(71). Upregulation and functional association with various types of cancer have been reported for SRSF3 (66)(67)(68)72) and hnRNP A1 (73-76), which we have identified here as two crucial trans-acting factors for alternative splicing of HPV18 pre-mRNAs.…”

Section: Discussionmentioning

confidence: 64%

“…To understand how the ESE functions in the promotion of RNA splicing, we analyzed the ESE sequence by searching for potential binding sites of trans-acting splicing factors that might regulate ESE function (11,34,(42)(43)(44)(45). As a result, we discovered that the identified ESE contains two putative SRSF3-binding motifs-SRSF3a, from nt 3522 to 3527, and SRSF3b, from nt 3539 to 3544 -and one putative SRSF1-binding A U1 binding motif of 11 nt (gray boxes) was attached to the 3= ends of pre-mRNAs 2, 4, 6, and 8 to enhance in vitro splicing.…”

Section: Resultsmentioning

confidence: 99%

“…Motif searching was conducted based on sequence homology to the SRSF3-binding sequences identified previously (34) or with SFmap software (http://sfmap.technion .ac.il/) (35,36) to identify binding motifs found in systematic evolution of ligands by exponential enrichment (SELEX). RNA pulldown assays were performed as described previously (11,34). Briefly, 5= biotin-labeled RNA oligonucleotides were conjugated to Neutroavidin beads (Thermo Fisher Scientific) and incubated with HeLa cell extract at 4°C overnight.…”

Section: Cell Lines Hek293 Cells (Human Embryonic Kidney Tissue-derimentioning

confidence: 99%

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Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCEExpression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.H igh-risk human papillomavirus (HPV) is associated with more than 95% of cervical cancer, 40 to 90% of anogenital cancer, and 10 to 60% of oropharyngeal cancer with geographic variation (1). Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regu...

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“…Finally, 20 potential osteosarcoma-associated proteins were selected to further validate the proteomic results. Among the 20 proteins, HUWE1, PCNA, GSN, ANXA1, AKAP12, and IDH2 have major roles in osteosarcoma tumorigenesis121314151617. MTHFD1, TSTA3, PGK1, HSPB1, MPST, HADHA, MCM5, CSE1L, LMNA, and MACF1 have been reported to be involved in tumorigenesis but not in osteosarcoma18192021222324252627.…”

Section: Resultsmentioning

confidence: 99%

CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival

Cheng

Lin

et al. 2017

Sci Rep

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To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

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A genome landscape of SRSF3-regulated splicing events and gene expression in human osteosarcoma U2OS cells

Cited by 103 publications

References 110 publications

HnRNP L is important for the expression of oncogene SRSF3 and oncogenic potential of oral squamous cell carcinoma cells

HnRNP L is important for the expression of oncogene SRSF3 and oncogenic potential of oral squamous cell carcinoma cells

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival

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