Protein kinase D activity is a risk biomarker in prostate cancer that drives cell invasion by a Snail/ERK dependent mechanism

Protein kinase D (PKD) family members play controversial roles in prostate cancer (PC). Thus, PKD1 is nearly absent in advanced tumours, where PKD2 and PKD3 are upregulated. Additionally, consequences of activation of these kinases on PC progression remain largely unclear. Here, we first investigated PKD function on PC cell motility, analysing the underlying molecular mechanisms. We find a striking decrease of Snail levels after PKD inhibition followed by cell migration and invasion impairment, demonstrating an unprecedented role of PKD activity on the regulation of this key transcription factor in PC progression. Specifically, we show that PKD2 activity mediates the effects of MEK/ERK pathway on Snail expression, establishing a joint function of ERK/ PKD2/Snail cascade in PC cell invasion regulation. These results led us to address the clinical relevance of the correlation between PKD2 and ERK activities with Snail abundance in samples from PC patients at different stages, analysing its impact on tumour prognosis and patients´survival. Importantly, this is the first study defining a direct correlation between active PKD2 and Snail levels, further linked to ERK activity. We also evidence that PKD2 activity is associated with important poor prognostic factors. Thus, PC patients with the expression pattern: active PKD2high/active ERKhigh/Snailhigh exhibit increased invasiveness and metastasis, and decreased survival. Our findings provide new insights for understanding the molecular mechanisms involved in PC progression, pinpointing the combination of active PKD2 and Snail levels, with the additional measurement of active ERK, as a confident biomarker to predict clinical outcome of patients with advanced PCD.C.-R., D.M.-M., and P.B. were recipients of grants from Comunidad de Madrid, Spain (grant numbers PEJ-2019-AI/BMD-14294, PEJD2018-PRE/BMD-8987, and 2017-T1/BMD-5704, respectively). T.I. received funding from Centro de Investigacion ´ Biom´edica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Spai

Hepatitis C virus-mediated Aurora B kinase inhibition modulates inflammatory pathway and viral infectivity

Chronic hepatitis C is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. DNA methylation and histone covalent modifications constitute crucial mechanisms of genomic instability in human disease, including liver fibrosis and hepatocellular carcinoma. The present work studies the consequences of HCV-induced histone modifications in early stages of infection. Methods Human primary hepatocytes and HuH7.5 cells were transiently transfected with the core protein of hepatitis C virus (HCV) genotypes 1a, 1b, and 2a. Infectious genotype 2a HCV in culture was also used. Results We show that HCV and core protein inhibit the phosphorylation of Serine 10 in histone 3. The inhibition is due to the direct interaction between HCV core and Aurora B kinase (AURKB) that results in a decrease of AURKB activity. HCV and core significantly downregulate NF-κB and COX-2 transcription, two proteins with anti-apoptotic and proliferative effects implicated in the control of the inflammatory response. AURKB depletion reduced HCV and core repression of NF-κB and COX-2 gene transcription and AURKB overexpression reversed the viral effect. AURKB abrogation increased HCV specific infectivity which was decreased when AURKB was overexpressed. Conclusions The core-mediated decrease of AURKB activity may play a role in the inflammatory pathway during the initial steps of viral infection, while ensuring HCV infectivityThis work was supported by grants BFU2009-11071 and BFU2011-23604 from Ministerio de Ciencia e Innovación, FIS: PI12/02146 and CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas) from Instituto de Salud Carlos III, Epistem Ltd and Fundación Ramón Areces. Dr Julie Sheldon was supported by a Juan de la Cierva contract from CSIC and Irene Francisco by a fellowship from Spanish Cancer Association (AECC) and Postgraduate studies from the Universidad Autónoma de Madri