title: Snf1-related kinase inhibits colon cancer cell proliferation through calcyclin-binding protein-dependent reduction of β-catenin.
abstract: Sucrose nonfermenting 1 (Snf1)-related kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase (AMPK); however, its function is not well characterized. We conducted a gene array to determine which genes are regulated by SNRK. The array demonstrated that SNRK overexpression increased the levels of genes involved in cell proliferation, including calcyclin-binding protein (CacyBP), a member of the ubiquitin ligase complex that targets nonphosphorylated β-catenin for degradation. We confirmed that SNRK increased CacyBP mRNA and protein, and decreased β-catenin protein in HCT116 and RKO colon cancer cells. Furthermore, SNRK inhibited colon cancer cell proliferation, and CacyBP down-regulation reversed the SNRK-mediated decrease in proliferation and β-catenin. SNRK overexpression also decreased β-catenin nuclear localization and target gene transcription, and β-catenin down-regulation reversed the effects of SNRK knockdown on proliferation. SNRK transcript levels were reduced in human colon tumors compared to normal tissue by 35.82%, and stable knockdown of SNRK increased colon cancer cell tumorigenicity. Our results demonstrate that SNRK is down-regulated in colon cancer and inhibits colon cancer cell proliferation through CacyBP up-regulation and β-catenin degradation, resulting in reduced proliferation signaling. These findings reveal a novel function for SNRK in the regulation of colon cancer cell proliferation and β-catenin signaling.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Rines
authors.forename: Michael A
authors.initials: MA
authors.lastname: Burke
authors.forename: Richard P
authors.initials: RP
authors.lastname: Fernandez
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C491778:CACYBP protein, human; C495270:CTNNB1 protein, human; D002135:Calcium-Binding Proteins; D051176:beta Catenin; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases