Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

Sui, Yan-Fang; Yang, Zhongxue; Xiong, Shiqin; Zhang, L; Blanchard, Kerry; Peiper, Stephen C.; Dynan, William S.; Tuan, Dorothy; Ko, Lan

doi:10.1038/sj.onc.1209847

Cited by 32 publications

(60 citation statements)

References 39 publications

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“…Although a previous study suggested that mRNA levels of CoAA were upregulated in several cancer cell lines (17), a significant population of cancer tissues exhibit smaller amounts of CoAA protein than normal tissues (see Table S1 in the supplemental material), supporting our previous findings of the tumor-suppressive activity of CoAA (16). Among these cancers, we chose to examine two cell lines, MCF7 and Ishikawa, representing breast cancer and endometrial cancer, respectively.…”

Section: Identification Of Ssa As a Coaa-interacting Proteinmentioning

confidence: 99%

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E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Kang

Jung

Qin

et al. 2014

Molecular and Cellular Biology

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Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G 1 /S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

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Section: Identification Of Ssa As a Coaa-interacting Proteinmentioning

confidence: 99%

“…Our laboratory and other laboratories have reported that coactivator activator (CoAA; gene symbol RBM14) plays a yin-yang function in oncogenesis (16,17). CoAA was originally reported as a protein interacting with the proto-oncogene for synovial sarcoma translocation (SYT) protein (18), suggesting its potential implication in tumorigenesis.…”

mentioning

confidence: 99%

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Kang

Jung

Qin

et al. 2014

Molecular and Cellular Biology

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“…ants of CoAA and RBM4-We have previously reported that gene amplification and its associated genetic alterations in oncogene CoAA deregulate CoAA pre-mRNA alternative splicing and potentially impact stem cell differentiation (27,28). At the 5Ј boundary of all identified amplicons, CoAA (RBM14), RBM4, and RBM4B coregulator genes are consecutively aligned and are conserved in mammals.…”

Section: Identification Of Coaz and Nccoaz As Trans-splicing Vari-mentioning

confidence: 99%

“…In stem cells, CoAA and CoAM regulate early stem cell differentiation through a switch of their alternative splicing at the stage of embryoid body cavitation (27). In human cancers the CoAA gene is amplified with the recurrent deletion of its 5Ј upstream regulatory sequence (28). We have shown that deletion of this regulatory sequence leads to defective switching between CoAA and CoAM (27).…”

mentioning

confidence: 98%

Functional Pre- mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation

Brooks

Wang

Yang

et al. 2009

Journal of Biological Chemistry

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Alternative splicing yields functionally distinctive gene products, and their balance plays critical roles in cell differentiation and development. We have previously shown that tumor-associated enhancer loss in coactivator gene CoAA leads to its altered alternative splicing. Here we identified two intergenic splicing variants, a zinc finger-containing coactivator CoAZ and a non-coding transcript ncCoAZ, between CoAA and its downstream corepressor gene RBM4. During stem/progenitor cell neural differentiation, we found that the switched alternative splicing and trans-splicing between CoAA and RBM4 transcripts result in lineage-specific expression of wild type CoAA, RBM4, and their variants. Stable expression of CoAA, RBM4, or their variants prevents the switch and disrupts the embryoid body formation. In addition, CoAA and RBM4 counter-regulate the target gene Tau at exon 10, and their splicing activities are subjected to the control by each splice variant. Further phylogenetic analysis showed that mammalian CoAA and RBM4 genes share common ancestry with the Drosophila melanogaster gene Lark, which is known to regulate early development and circadian rhythms. Thus, the trans-splicing between CoAA and RBM4 transcripts may represent a required regulation preserved during evolution. Our results demonstrate that a linked splicing control of transcriptional coactivator and corepressor is involved in stem/progenitor cell differentiation. The alternative splicing imbalance of CoAA and RBM4, because of loss of their common enhancer in cancer, may deregulate stem/progenitor cell differentiation.From the initial discovery of RNA splicing (1, 2) to recent advanced genomic studies (3), a large body of evidence suggests that alternative splicing as an integral part of gene regulation profoundly impacts biological and pathological functions (4). In the human genome, although ϳ20,000 protein-coding genes exist, more than 90% of multi-exon genes are alternatively spliced (3,5,6). Thus, alternative pre-mRNA splicing contributes greatly to proteome diversity without increasing the number of genes (7,8). Alternative splicing can be cell-and tissuespecific, which is particularly important at the early developmental stages (9). The wild type and variant proteins often exert overlapping but distinct functions whose balance is controlled by the choice of alternative splicing. Aberrant splicing patterns may disrupt the normal functional balance of isoforms, which in turn impairs cell differentiation and induces disease or cancer (10, 11).Pre-mRNA splicing is a process of joining exons and splicing out introns. In addition to constitutive splicing events, exons can be alternatively spliced. This includes exon skipping, alternative 5Ј and 3Ј splicing, mutually exclusive exons, intron retention, and alternative transcription start or stop sites (12). The cis-splicing mechanism involves splicing within one pre-mRNA molecule. In contrast, significant evidence supports that trans-splicing can occur at a much lower frequency by joining exons f...

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“…While these results may be influenced by overlapping donors, they provide evidence that splicing is more similar in tissues with shared cell type compositions (Qian et al 2005; Ong and Corces 2011; The GTEx Consortium 2017). (Auboeuf et al 2002(Auboeuf et al , 2004Sui et al 2007 (Vareli et al 2000). 20…”

Section: Comparison Between Twns Reveals Per-tissue Hub Genesmentioning

confidence: 99%

Co-expression networks reveal the tissue-specific regulation of transcription and splicing

et al. 2017

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Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.

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Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

Cited by 32 publications

References 39 publications

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Functional Pre- mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation

Co-expression networks reveal the tissue-specific regulation of transcription and splicing

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Gene amplification and associated loss of 5′ regulatory sequences of CoAA in human cancers

Cited by 32 publications

References 39 publications

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G1/S Arrest To Promote Breast Tumorigenicity

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G1/S Arrest To Promote Breast Tumorigenicity

Functional Pre- mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation

Co-expression networks reveal the tissue-specific regulation of transcription and splicing

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E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity