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3'READS + RIP defines differential Staufen1 binding to alternative 3'UTR isoforms and reveals structures and sequence motifs influencing binding and polysome association.

ABSTRACT: Staufen1 (STAU1) is an RNA-binding protein (RBP) that interacts with double-stranded RNA structures and has been implicated in regulating different aspects of mRNA metabolism. Previous studies have indicated that STAU1 interacts extensively with RNA structures in coding regions (CDSs) and 3'-untranslated regions (3'UTRs). In particular, duplex structures formed within 3'UTRs by inverted-repeat Alu elements (IRAlus) interact with STAU1 through its double-stranded RNA-binding domains (dsRBDs). Using 3' region extraction and deep sequencing coupled to ribonucleoprotein immunoprecipitation (3'READS + RIP), together with reanalyzing previous STAU1 binding and RNA structure data, we delineate STAU1 interactions transcriptome-wide, including binding differences between alternative polyadenylation (APA) isoforms. Consistent with previous reports, RNA structures are dominant features for STAU1 binding to CDSs and 3'UTRs. Overall, relative to short 3'UTR counterparts, longer 3'UTR isoforms of genes have stronger STAU1 binding, most likely due to a higher frequency of RNA structures, including specific IRAlus sequences. Nevertheless, a sizable fraction of genes express transcripts showing the opposite trend, attributable to AU-rich sequences in their alternative 3'UTRs that may recruit antagonistic RBPs and/or destabilize RNA structures. Using STAU1-knockout cells, we show that strong STAU1 binding to mRNA 3'UTRs generally enhances polysome association. However, IRAlus generally have little impact on STAU1-mediated polysome association despite having strong interactions with the protein. Taken together, our work reveals complex interactions of STAU1 with its cognate RNA substrates. Our data also shed light on distinct post-transcriptional fates for the widespread APA isoforms in mammalian cells.

SUBMITTER: Zheng D

PROVIDER: S-EPMC7566578 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProstate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer.MethodsUsing a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated.ResultsWe show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase.ConclusionsCollectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.

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3'READS + RIP defines differential Staufen1 binding to alternative 3'UTR isoforms and reveals structures and sequence motifs influencing binding and polysome association.

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