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Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer.

ABSTRACT: Recent genome-wide association studies have identified fibroblast growth factor receptor (FGFR)2 as one of a few candidate genes linked with breast cancer susceptibility. In particular, the disease-predisposing allele of FGFR2 is inherited as a 7.5-kb region within intron 2 that harbors eight single nucleotide polymorphisms. The relationship between these single nucleotide polymorphisms and FGFR2 gene expression remains unclear. Here we show the common occurrence of polymorphisms within the intron 2 region in a panel of 10 breast cancer cell lines. High FGFR2-expressing cell lines such as MCF-7 cells displayed polymorphic sequences with constitutive histone acetylation at multiple intron 2 sequences harboring putative transcription binding sites. Knockdown of Runx2 or CCAAT enhancer binding protein beta in these cells resulted in diminished endogenous FGFR2 gene expression. In contrast FGFR2-negative MDA-231 cells were wild type and showed evidence of histone 3/4 deacetylation at the rs2981578, rs10736303, and rs7895676 disease-associated alleles that harbor binding sites for Runx2, estrogen receptor, and CCAAT enhancer binding protein beta, respectively. Histone deacetylation inhibition with trichostatin A resulted in enhanced acetylation at these intron 2 sites, an effect associated with robust FGFR2 reexpression. Isoform analysis proved reexpression of the FGFR2-IIIc variant the splicing of which was positively influenced by trichostatin A-mediated recruitment of the Fas-activated serine/threonine phosphoprotein survival protein. Our findings highlight the potential role of histone acetylation in modulating access to selected polymorphic sites within intron 2 as well as downstream splicing sites in generating variable FGFR2 levels and isoforms in breast cancer.

SUBMITTER: Zhu X

PROVIDER: S-EPMC2737561 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer.

Zhu Xuegong X Asa Sylvia L SL Ezzat Shereen S

Molecular endocrinology (Baltimore, Md.) 20090604 9

Recent genome-wide association studies have identified fibroblast growth factor receptor (FGFR)2 as one of a few candidate genes linked with breast cancer susceptibility. In particular, the disease-predisposing allele of FGFR2 is inherited as a 7.5-kb region within intron 2 that harbors eight single nucleotide polymorphisms. The relationship between these single nucleotide polymorphisms and FGFR2 gene expression remains unclear. Here we show the common occurrence of polymorphisms within the intr ...[more]

PMID: 19497954

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Project description:Background: Splicing factors are essential for nascent pre-mRNA processing and critical in cancer progression, suggesting that proteins with splicing functions represent potential molecular targets for cancer therapy. Here, we investigate the role of splicing factors in glioblastoma multiforme (GBM) progression and the possibility of targeting them for the treatment of the disease. Methods: The TCGA and CGGA public databases were used to screen for differentially expressed mRNA splicing factors. Immunohistochemistry and qRT-PCR were used to analyze the expression of non-POU domain-containing octamer-binding protein (NONO), a Drosophila behavior human splicing (DBHS) protein. Knockdown/overexpression of NONO with siRNA and lentiviral expression constructs was used to examine cell growth, apoptosis, and invasion in GBM cells. RNA sequencing was used to identify potential downstream molecular targets of NONO. RIP-PCR and RNA pulldown were used to determine the interaction between NONO and pre-mRNA. JC-1 staining and the seahorse assay were performed to assess redox homeostasis. Results: Expression of NONO was increased in GBM samples and associated with poor survival in patients (P = 0.04). Knockdown of NONO suppressed GBM growth, and overexpression of NONO promoted GBM tumorigenesis in vitro and in vivo. RNA sequencing-based transcriptomic profiling confirmed that knockdown of NONO in U251 and P3 cells resulted in global intron retention of pre-mRNA and led to abnormal splicing of specific pre-mRNAs for GPX1 and CCN1. NONO bound to a consensus motif in the intron of GPX1 pre-mRNA in association with another DBHS protein family member, PSPC1. Knockdown of NONO impaired tumor growth, invasion, and redox homeostasis through aberrant splicing of GPX1. Finally, Auranofin, a small molecule inhibitor of NONO, suppressed GBM tumor growth in an orthotopic xenograft model in mice. Conclusions: We demonstrated that intron retention was a critical alternative RNA splicing event to occur in GBM progression, and that NONO was a key regulator of mRNA splicing in GBM. Targeting NONO represents a novel, potential therapeutic strategy for GBM treatment.

Dataset Information

Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer.

Publications

Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer.

Similar Datasets

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