title: Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer.
abstract: Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell-cycle progression, induced cell death, and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death, and enhanced CREB1 activity. Treatment with a small-molecule SIK2 inhibitor (ARN-3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Because CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and while SIK2 knockdown or overexpression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete.
  
  
  CONCLUSIONS
  This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell-cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors.
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bon
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Karan
authors.initials: K
authors.lastname: Wadhwa
authors.affiliation: Microscopy and Imaging Core, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schreiner
authors.affiliation: Genomics Core, Cambridge Research Institute, Cambridge, CB2 ORE, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Osborne
authors.affiliation: Bioinformatics Core, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.affiliation: Health Care Innovation, Philips Research, Eidhoven, Netherlands.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Visser
authors.affiliation: Molecular Diagnostics, Philips Research, Eindhoven, Netherlands.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS and Nuffield Department of Obstetrics and Gynaecology, University of Oxford, OX3 9DU, UK.
authors.forename: Ahmed Ashour
authors.initials: AA
authors.lastname: Ahmed
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.|Department of Urology, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.|Department of Oncology, University of Cambridge, Cambridge, CB2 2QQ, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Uro-oncology Research Group, Cambridge Research Institute, Cambridge, CB2 0RE, UK.|Department of Urology, Oslo University Hospital, 0424 Oslo, Norway.|Department of Cancer Prevention, Oslo University Hospital, 0424 Oslo, Norway.|Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo and Oslo University Hospital, N-0349, Oslo, Norway.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
mesh_terms: D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000097:blood* / Q000235:genetics; D000090063:Proto-Oncogene Mas; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001323:Autoantibodies; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases