9 results found
Fletcher CE, 2019, The Role of Splicing Regulators in the Emergence of Treatment-induced Neuroendocrine Prostate Cancer: The Next Generation of Drug Targets?, EUROPEAN UROLOGY, Vol: 76, Pages: 167-169, ISSN: 0302-2838
Fletcher C, Sulpice E, Combe S, et al., 2019, Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer, Oncogene, Vol: 38, Pages: 5700-5724, ISSN: 0950-9232
Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even inadvanced ‘castrate-resistant’ disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors dramatically reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9kb 3’UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively-active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC the
Fletcher CE, 2017, AR-v7 liquid biopsy for treatment stratification in prostate cancer: how close are we?, Current Opinion in Urology, ISSN: 0963-0643
Fletcher CE, Godfrey JD, Shibakawa A, et al., 2017, A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis, Nucleic Acid Research, Vol: 45, Pages: 2809-2828, ISSN: 2159-3345
Regulation of microRNA (miR) biogenesis is complex and stringently controlled. Here, we identify the kinase GSK3ß as a important modulator of miR biogenesis at Microprocessor level. Repression of GSK3ß activity reduces Drosha activity towards pri-miRs, leading to accumulation of unprocessed pri-miRs and reduction of mature pri-miRs without altering levels or cellular locations of miR biogenesis proteins...
Fletcher CE, Bevan CL, Sita-Lumsden A, et al., 2015, Circulating Nucleic Acids as Prostate Cancer Biomarkers, Epigenetic Biomarkers and Diagnostics, Editors: Garcia-Giménez, Publisher: Elsevier
Fletcher CE, Dart DA, Bevan CL, 2014, Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers, Endocrine-Related Cancer, Vol: 21, Pages: R409-R429, ISSN: 1479-6821
Hormones are key drivers of cancer development. To date, interest has largely been focussed on the classical model of hormonal gene regulation, but there is increasing evidence for a role of hormone signalling pathways in post-translational regulation of gene expression. In particular, a complex and dynamic network of bi-directional interactions with microRNAs (miRs) at all stages of biogenesis and during target gene repression is emerging. miRs, which act mainly by negatively regulating gene expression through association with 3′-UTRs of mRNA species, are increasingly understood to be important in development, normal physiology and pathogenesis. Given recent demonstrations of altered miR profiles in a diverse range of cancers, their ability to function as oncogenes or tumour suppressors, and hormonal regulation of miRs, understanding mechanisms by which miRs are generated and regulated is vitally important. miRs are transcribed by RNA polymerase II and then processed in the nucleus by the Drosha-containing Microprocessor complex and in the cytoplasm by Dicer, before mature miRs are incorporated into the RNA-induced silencing complex. It is increasingly evident that multiple cellular signalling pathways converge upon the miR biogenesis cascade, adding further layers of regulatory complexity to modulate miR maturation. This review summarises recent advances in identification of novel components and regulators of the Microprocessor and Dicer complexes, with particular emphasis on the role of hormone signalling pathways in regulating their activity. Understanding hormone regulation of miR production and how this is perturbed in cancer are critical for the development of miR-based therapeutics and biomarkers.
Sita-Lumsden A, Fletcher CE, Dart DA, et al., 2013, Circulating nucleic acids as biomarkers of prostate cancer, BIOMARKERS IN MEDICINE, Vol: 7, Pages: 867-877, ISSN: 1752-0363
Frampton AE, Fletcher CE, Gall TMH, et al., 2013, Circulating peripheral blood mononuclear cells exhibit altered miRNA expression patterns in pancreatic cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 13, Pages: 425-430, ISSN: 1473-7159
Fletcher CE, Dart DA, Sita-Lumsden A, et al., 2012, Androgen-regulated processing of the oncomir MiR-27a, which targets Prohibitin in prostate cancer, HUMAN MOLECULAR GENETICS, Vol: 21, Pages: 3112-3127, ISSN: 0964-6906
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