Mutations affecting Gαq proteins are pervasive in uveal melanoma (UM), suggesting they ‘drive’ UM pathogenesis. The ERK1/2-MAPK pathway is critical for cutaneous melanoma development and consequently an important therapeutic target. Defining the contribution of ERK1/2-MAPK signalling to UM development has been hampered by the lack of an informative animal model that spontaneously develops UM. Towards this end, we engineered transgenic zebrafish to express oncogenic GNAQQ209P in the melanocyte lineage. This resulted in hyperplasia of uveal melanocytes, but with no evidence of malignant progression, nor perturbation of skin melanocytes. Combining expression of oncogenic GNAQQ209P with p53 inactivation resulted in earlier onset and even more extensive hyperplasia of uveal melanocytes that progressed to UM. Immunohistochemistry revealed only weak immunoreactivity to phosphorylated (p)ERK1/2 in established uveal tumours—in contrast to strong immunoreactivity in oncogenic RAS-driven skin lesions—but ubiquitous positive staining for nuclear Yes-associated protein (YAP). Moreover, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ or phospholipase C-beta (PLC-β) inhibition in the majority of human UM cell lines we tested harbouring GNAQ mutations. In summary, our findings demonstrate a weak correlation between oncogenic GNAQQ209P mutation and sustained ERK1/2-MAPK activation, implying that ERK1/2 signalling is unlikely to be instrumental in the maintenance of GNAQQ209P-driven UMs.

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RNA‐binding proteins (RBPs) and noncoding (nc)RNAs (such as microRNAs, long ncRNAs, and others) cooperate within a post‐transcriptional network to regulate the expression of genes required for many aspects of cancer behavior including its sensitivity to chemotherapy. Here, using an RBP‐centric approach, we explore the current knowledge surrounding contributers to post‐transcriptional gene regulation (PTGR) in ovarian cancer and identify commonalities that hint at the existence of an evolutionarily conserved core PTGR network. This network regulates survival and chemotherapy resistance in the contemporary context of the cancer cell. There is emerging evidence that cancers become dependent on PTGR factors for their survival. Further understanding of this network may identify innovative therapeutic targets as well as yield crucial insights into the hard‐wiring of many malignancies, including ovarian cancer. WIREs RNA 2018, 9:e1432. doi: 10.1002/wrna.1432This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional ImplicationsTranslation > Translation MechanismsRNA in Disease and Development > RNA in Disease

LARP1 is an oncogenic RNA-binding protein required for ribosome biogenesis and cancer cell survival. From published in vitro studies, there is disparity over which of two different LARP1 protein isoforms (termed the long LI-LARP1 and short SI-LARP1) is the canonical. Here, after conducting a series of biochemical and cellular assays, we conclude that LI-LARP1 (NM_033551.3 > NP_056130.2) is the dominantly expressed form. We observe that SI-LARP1 (NM_015315.5> NP_056130.2) is epigenetically repressed and that this repression is evolutionarily conserved in all but a small subclade of mammalian species. As with other LARP family members, there are multiple potential LARP1 mRNA isoforms that appear to be censored within the nucleus. The capacity of the cell to modulate splicing and expression of these apparently 'redundant' mRNAs hints at contextually specific mechanisms of LARP1 expression.

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The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

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