Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT

Harvey, Samuel E.; Xu, Yilin; Lin, Xiaodan; Gao, Xin D.; Qiu, Yin Long; Ahn, Jaegyoon; Xiao, Xinshu; Cheng, Chonghui

doi:10.1261/rna.066712.118

Cited by 59 publications

(58 citation statements)

References 62 publications

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“…Interestingly, several SF-induced spliced isoforms detected in this study (Figure 3 and Table S3), i.e., ARHGEF11+ex38,RALGPS2∆ex10,MLPH+ex9,, and APLP2∆ex7, were previously associated with EMT in mammary epithelial cells (Brown et al, 2011;Harvey et al, 2018;Shapiro et al, 2011;Warzecha et al, 2010), consistent with the invasive phenotype we observe in SF-OE cells.…”

Section: The Splicing Repertoire Of Sr Proteins In Human Mammary Cellsupporting

confidence: 88%

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Das

Akerman

et al. 2019

Preprint

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Misregulation of alternative splicing is a hallmark of human tumors; yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer, and uncover differences and redundancies in their targets and biological functions. We first identify splicing factors frequently altered in human breast tumors, and then assay their oncogenic functions using breast organoid models.Importantly we demonstrate that not all splicing factors affect mammary tumorigenesis. Specifically, upregulation of either SRSF4, SRSF6 or TRA2β promotes cell transformation and invasion. By characterizing the targets of theses oncogenic factors, we identify a shared set of spliced genes associated with well-established cancer hallmarks. Finally, we demonstrate that the splicing factor TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast-cancer-patient survival.3

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Section: The Splicing Repertoire Of Sr Proteins In Human Mammary Cellsupporting

confidence: 88%

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Das

Akerman

et al. 2019

Preprint

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“…hnRNP H might also work as enhancer, if the binding site is downstream the 5′ ss, or inhibitor, if the binding site is located within the exon (Z. Wang & Burge, ). In general, GU‐rich sequences are targets for hnRNP M (Harvey et al, ), G/A motifs are bound by hnRNP A2/B1 and G‐rich sequences are bound by hnRNP F (Huelga et al, ).…”

Section: Splicing Alterations In Cancermentioning

confidence: 99%

Splicing and cancer: Challenges and opportunities

2019

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Constitutive splicing is favored in strong splice sites, which have the conserved consensus sequences at 5 0 (CAG|GUAAGU) and 3 0 (NYAG|G) splice sites. Exons are usually shorter sequences, ranging from 50 to 250 bp, whereas introns can have broader length variation, from <100 bp to more than 1,000 bp, and around 20% of human introns are larger than 5 kb (Lander et al., 2001). In addition to constitutive exon splicing, the presence of alternative splice sites leads to variable ways to mature an mRNA ( Figure 2). Exons and introns might host alternative splice sites, which are similar to, but usually not as strong as, consensus splice sites (Fu & Ares, 2014;Kornblihtt et al., 2013). If a 5 0 or 3 0 alternative site lies within an exon, part of this exon might be read as an intron. Also, alternative splicing can lead to exon skipping, in which a constitutive 3 0 splice site fails to be recognized and assembly of spliceosome proceeds to the next available 3 0 splice site, which can result in exclusion of an exon. Alternatively, 5 0 splice sites might not be read as well, resulting in intron retention. In some transcripts, a mutual exclusion of exons might take place generating different messages . Cryptic splice sites are similar to consensus sites, but they are usually recognized only after a mutation in the gene, or of a spliceosome component, leading to alterations in the final message. In breast cancer, mutations in splicing factor 3B subunit 1 (SF3B1), for example, induce the use of cryptic 3 0 splice sites (DeBoever et al., 2015). Single nucleotide variants (SNVs) of 1,812 tumor samples were analyzed by whole-exome sequencing and revealed exon skipping and intron retention were among the most frequently observed alternative splicing events (Jung et al., 2015; Box 1).Alternative splicing mechanisms are dependent on recognition of splice site sequences in the pre-mRNA, which in turn depends on both the strength of sequences as well as the presence of proteins and signals that guide the spliceosome to these regions. Alternative exons in humans and mice are surrounded by more conserved regulatory sequences than constitutive exons, indicating the former ones are under strict regulation. Consistently, 30-50% of ISEs are located nearby alternative exons (Yeo, Van Nostrand, & Liang, 2007). Interestingly, ISEs and ESSs show a positional overlap in different pre-mRNA substrates, indicating the regulation depends on their positioning with respect to the 5 0 upstream exon and the bound proteins (Y. Wang et al., 2012). The ISSs can interfere with exon inclusion in different pre-mRNAs, and regulate 5 0 splice site choice, therefore, exerting alternative splicing regulation (Y. Wang et al., 2013). In this sense, mutations in exonic and intronic sequences are critical and might affect the balance of regulatory sequences and also their activity, since most effects in splicing are location-dependent. Intronic mutations are commonly associated with nonsense-mediated decay responses, caused by an increased rate of premature stop ...

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“…Aberrant activation of EMT enables primary epithelial cancer cells to acquire advantageous mesenchymal properties, including invasion and drug resistance, ultimately allowing the survival of cancer cells within the circulatory system and subsequent colonization of distant organs [4][5][6] . Whereas several transcription factors, such as Twist, Snail, and Zeb1/2, and signaling pathways, including TGFβ, have been characterized as potent inducers of EMT 6,7 , growing evidence has suggested that alternative RNA splicing acts as a critical layer of regulation impinging on EMT [8][9][10][11] .…”

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confidence: 99%

The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing

Harvey

Zheng

et al. 2020

Nat Commun

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Alternative splicing has been shown to causally contribute to the epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein-protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.

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Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT

Cited by 59 publications

References 62 publications

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis

Splicing and cancer: Challenges and opportunities

The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing

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