Snf1‐related kinase inhibits colon cancer cell proliferation through calcyclin‐binding protein‐dependent reduction of β‐catenin

• Published in: The FASEB journal 2012-11, Vol.26 (11), p.4685-4695
• Main Authors: Rines, Amy K., Burke, Michael A., Fernandez, Richard P., Volpert, Olga V., Ardehali, Hossein
• Format: Article
• Language: English
• Subjects: beta Catenin - genetics; beta Catenin - metabolism; CacyBP; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Gene Expression Regulation, Neoplastic - physiology; Gene Knockdown Techniques; Humans; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Research Communications; Signal Transduction - physiology; SNRK; Transcriptome
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.12-212282

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.—Rines, A. K., Burke, M. A., Fernandez, R. P., Volpert, O. V., Ardehali, H. Snf1‐related kinase inhibits colon cancer cell proliferation through calcyclin binding protein‐dependent reduction of β‐catenin. FASEB J. 26, 4685–4695 (2012). www.fasebj.org