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Munkley J.,Northumbria University | Livermore K.E.,Northumbria University | McClurg U.L.,Northumbria University | Kalna G.,Cancer Research UK Research Institute | And 12 more authors.
Oncoscience | Year: 2015

Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85α) and PIK3R3 (p55γ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110α catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85α protein by the AR results in destabilisation of the PI3K p110α catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.

Munkley J.,Northumbria University | Oltean S.,University of Bristol | Vodak D.,University of Oslo | Wilson B.T.,Northumbria University | And 20 more authors.
Oncotarget | Year: 2015

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castrationresistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.

Shepherd M.,University of Exeter | Shepherd M.,NIHR Exeter Clinical Research Facility | Cropper J.,Leeds Teaching Hospitals NHS Trust
Journal of Diabetes Nursing | Year: 2013

Although type 1 diabetes accounts for most cases of diabetes presenting in childhood, skills and knowledge enabling paediatric teams to confidently identify other forms of diabetes are clearly required. Ensuring correct diagnosis by recognising cases of "non-type 1" diabetes in children and young people is crucial as it has implications for treatment and follow up. This article highlights three cases of diabetes presenting in children with features suggesting potential monogenic causes of diabetes. The cases include hepatocyte nuclear factor 1-alpha maturity onset diabetes of the young (MODY), glucokinase MODY and KCNJ11 neonatal diabetes. The implications of the correct diagnosis are also discussed.

Morel K.,University of Sussex | Colclough K.,Royal Devon and Exeter NHS Healthcare Trust | Vaughan N.,University of Sussex | Shepherd M.,Royal Devon and Exeter NHS Healthcare Trust | Shepherd M.,NIHR Exeter Clinical Research Facility
Journal of Diabetes Nursing | Year: 2013

Monogenic diabetes is poorly recognised but identification is important as many people may be successfully managed with sulphonylureas rather than insulin (Pearson et al, 2000; Stride and Hattersley, 2002; Pearson et al, 2003; Shepherd et al, 2003; Hattersley, 2005). Ensuring the correct diagnosis also allows appropriate follow up and counselling of family members (Shepherd et al, 2010). The Genetic Diabetes Nurse (GDN) project was set up in 2002 to increase awareness of monogenic diabetes (Dudding et al, 2005; Shepherd et al, 2005) and prior to the appointment of a GDN for Sussex in 2005, only one person had a confirmed diagnosis of monogenic diabetes in the Brighton and Hove area. This paper describes how training a GDN improved care through the identification of 54 people with monogenic diabetes and the establishment of a specialist clinic.

Munkley J.,Northumbria University | Vodak D.,University of Oslo | Livermore K.E.,Northumbria University | James K.,Northumbria University | And 13 more authors.
EBioMedicine | Year: 2016

Steroid androgen hormones play a key role in the progression and treatment of prostate cancer, with androgen deprivation therapy being the first-line treatment used to control cancer growth. Here we apply a novel search strategy to identify androgen-regulated cellular pathways that may be clinically important in prostate cancer. Using RNASeq data, we searched for genes that showed reciprocal changes in expression in response to acute androgen stimulation in culture, and androgen deprivation in patients with prostate cancer. Amongst 700 genes displaying reciprocal expression patterns we observed a significant enrichment in the cellular process glycosylation. Of 31 reciprocally-regulated glycosylation enzymes, a set of 8 (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3) were significantly up-regulated in clinical prostate carcinoma. Androgen exposure stimulated synthesis of glycan structures downstream of this core set of regulated enzymes including sialyl-Tn (sTn), sialyl LewisX (SLeX), O-GlcNAc and chondroitin sulphate, suggesting androgen regulation of the core set of enzymes controls key steps in glycan synthesis. Expression of each of these enzymes also contributed to prostate cancer cell viability. This study identifies glycosylation as a global target for androgen control, and suggests loss of specific glycosylation enzymes might contribute to tumour regression following androgen depletion therapy. © 2016 The Authors.

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