Stau1 is a pluripotent RNA-binding protein that is responsible for the post-transcriptional regulation of a multitude of transcripts. Here, we observed that lung cancer patients with a high Stau1 expression have a longer recurrence free survival. Strikingly, Stau1 did not impair cell proliferation in vitro, but rather cell migration and cell adhesion. In vivo, Stau1 depletion favored tumor progression and metastases development. In addition, Stau1 depletion strongly impaired vessel maturation. Among a panel of candidate genes, we specifically identified the mRNA encoding the cell adhesion molecule Thrombospondin 1 (THBS1) as a new target for Staufen-mediated mRNA decay. Altogether, our results suggest that regulation of THBS1 expression by Stau1 may be a key process involved in lung cancer progression.

Staufen 1 (STAU1) is an RNA-binding protein that is essential in untransformed cells. In cancer cells, it is rather STAU1 overexpression that impairs cell proliferation. In this paper, we show that a modest increase in STAU1 expression in cancer cells triggers apoptosis as early as 12 h post-transfection and impairs proliferation in non-apoptotic cells for several days. Interestingly, a mutation that mimics the phosphorylation of STAU1 serine 20 is sufficient to cause these phenotypes, indicating that serine 20 is at the heart of the molecular mechanism leading to apoptosis. Mechanistically, phosphomimicry on serine 20 alters the ability of STAU1 to regulate translation and the decay of STAU1-bound mRNAs, indicating that the posttranscriptional regulation of mRNAs by STAU1 controls the balance between proliferation and apoptosis. Unexpectedly, the expression of RBD2^S20D, the N-terminal 88 amino acids with no RNA-binding activity, is sufficient to induce apoptosis via alteration, in trans, of the posttranscriptional functions of endogenous STAU1. These results suggest that STAU1 is a sensor that controls the balance between cell proliferation and apoptosis, and, therefore, may be considered as a novel therapeutic target against cancer.

Staufen1 (STAU1) is an RNA-binding protein involved in the posttranscriptional regulation of mRNAs. We report that a large fraction of STAU1 localizes to the mitotic spindle in the colorectal cancer HCT116 and in the non-transformed hTERT-RPE1 cells. Spindle-associated STAU1 partly co-localizes with ribosomes and active sites of translation. We mapped the molecular determinant required for STAU1/spindle association within the first 88 N-terminal amino acids, a domain that is not required for RNA binding. Interestingly, transcriptomic analysis of purified mitotic spindles reveals that 1054 mRNAs as well as the precursor ribosomal RNA and lncRNAs and snoRNAs involved in ribonucleoprotein assembly and processing are enriched on spindles compared to cell extracts. STAU1 knockout causes the displacement of the pre-rRNA and of 154 mRNAs coding for proteins involved in actin cytoskeleton organization and cell growth, highlighting a role for STAU1 in mRNA trafficking to spindle. These data demonstrate that STAU1 controls the localization of sub-populations of RNAs during mitosis and suggests a novel role of STAU1 in pre-rRNA maintenance during mitosis, ribogenesis and/or nucleoli reassembly. SUMMARY STATEMENT: Proper localization and functions of macromolecules during cell division are crucial to ensure survival and proliferation of daughter cells.

This study describes a very interesting new method for the analysis of translation initiation of endogenous mRNAs in vivo. mRNAs are cross-linked to 40S ribosomes and immuno-precipitated using antibodies against single translational initiation factors prior to deep sequencing of the 40S footprints. This technique allows a very accurate analysis of 40S-bound factors during ribosome-scanning. Using this method, Bohlen et al. showed that the initiating 40S ribosome is tethered to the 5' cap during the entire scanning process, indicating that only one ribosome scans a 5’UTR at a time. Interestingly, this study also showed that eIFs bounds to 40S ribosomes are still associated with the 80S translating ribosomes for a half-length of approximately 12 codons. This likely explains how translation re-initiation can occur after a short uORF, but not after main ORFs, which are significantly longer. This method is promising for a systematic analysis of specific translational initiation mechanisms and of the components involved. It may, for example, facilitate elucidation of IRES-dependent translational initiation under stress conditions.