CK2α/CSNK2A1 Phosphorylates SIRT6 and Is Involved in the Progression of Breast Carcinoma and Predicts Shorter Survival of Diagnosed Patients.

Abstract

Recently, the roles of sirtuins (SIRTs) in tumorigenesis have been of interest to oncologists, and protein kinase CK2 α1 (CSNK2A1) has been shown to be involved in tumorigenesis by phosphorylating various proteins, including SIRT1. Therefore, we evaluated the roles of CSNK2A1, SIRT6, and phosphorylated SIRT6 and their relationships in breast carcinoma. Nuclear expression of CSNK2A1 and SIRT6 predicted shorter overall survival and relapse-free survival by multivariate analysis. Inhibition of CSNK2A1 decreased the proliferative and invasive activity of cancer cells. In addition, CSNK2A1 was bound to SIRT6 and phosphorylated SIRT6; evidence for this is provided from immunofluorescence staining, co-immunoprecipitation of CSNK2A1 and SIRT6, a glutathione S-transferase pull-down assay, an in vitro kinase assay, and transfection of mutant CSNK2A1. Knockdown of SIRT6 decreased the proliferation and invasiveness of cancer cells. Overexpression of SIRT6 increased proliferation, but mutation at the Ser338 phosphorylation site of SIRT6 inhibited the proliferation of MCF7 cells. Moreover, both knockdown of SIRT6 and a mutation at the phosphorylation site of SIRT6 decreased expression of matrix metallopeptidase 9, β-catenin, cyclin D1, and NF-κB. Especially, SIRT6 expression was associated with the nuclear localization of β-catenin. This study demonstrates that CSNK2A1 and SIRT6 are indicators of poor prognosis for breast carcinomas and that CSNK2A1-mediated phosphorylation of SIRT6 might be involved in the progression of breast carcinoma.

• Authors: Jun Sang Bae, See-Hyoung Park, Urangoo Jamiyandorj, Kyoung Min Kim, Sang Jae Noh, Jung Ryul Kim, Hye Jeong Park, Keun Sang Kwon, Sung Hoo Jung, Ho Sung Park, Byung-Hyun Park, Ho Lee, Woo Sung Moon, Karl G Sylvester, Kyu Yun Jang
• Journal: The American journal of pathology (Am J Pathol) Vol. 186 Issue 12 Pg. 3297-3315 (12 2016) ISSN: 1525-2191 [Electronic] United States
• PMID: 27746184 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CCND1 protein, human
• NF-kappa B
• beta Catenin
• Cyclin D1
• CSNK2A1 protein, human
• Casein Kinase II
• SIRT6 protein, human
• Sirtuins

Topics

• Breast Neoplasms (diagnosis, genetics, pathology)
• Casein Kinase II (genetics, metabolism)
• Cell Proliferation
• Cyclin D1 (metabolism)
• Disease Progression
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• Mutation
• NF-kappa B (metabolism)
• Phosphorylation
• Prognosis
• Sirtuins (genetics, metabolism)
• beta Catenin (metabolism)