Centromere protein F (CENPF), a microtubule binding protein, modulates cancer metabolism by regulating pyruvate kinase M2 phosphorylation signaling. Issue 24 (17th December 2018)

• Record Type: Journal Article
• Authors: Shahid, Muhammad; Lee, Min Young; Piplani, Honit; Andres, Allen M.; Zhou, Bo; Yeon, Austin; Kim, Minjung; Kim, Hyung L.; Kim, Jayoung
• Is Part Of: Cell cycle. Volume 17:Issue 24(2018)
• Page Start: 2802
• Page End: 2818
• Publication Date: 2018-12-17
• Subjects: CENP-F -- prostate cancer -- mitochondria; Cell cycle -- Periodicals; 571.84377
• DOI: 10.1080/15384101.2018.1557496
• Languages: English
• ISSNs: 1538-4101

Abstract

ABSTRACT: Prostate cancer (PC) is the most commonly diagnosed cancer in men and is the second leading cause of male cancer-related death in North America. Metabolic adaptations in malignant PC cells play a key role in fueling the growth and progression of the disease. Unfortunately, little is known regarding these changes in cellular metabolism. Here, we demonstrate that centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, is mechanically linked to altered metabolism and progression in PC. Using the CRISPR-Cas9 system, we silenced the gene for CENPF in human PC3 cells. These cells were found to have reduced levels of epithelial-mesenchymal transition markers and inhibited cell proliferation, migration, and invasion. Silencing of CENPF also simultaneously improved sensitivity to anoikis-induced apoptosis. Mass spectrometry analysis of tyrosine phosphorylated proteins from CENPF knockout (CENPF KO ) and control cells revealed that CENPF silencing increased inactive forms of pyruvate kinase M2, a rate limiting enzyme needed for an irreversible reaction in glycolysis. Furthermore, CENPF KO cells had reduced global bio-energetic capacity, acetyl-CoA production, histone acetylation, and lipid metabolism, suggesting that CENPF is a critical regulator of cancer metabolism, potentially through its effects on mitochondrial functioning. Additional quantitative immunohistochemistry and imaging analyzes on a series of PC tumor microarrays demonstrated that CENPF expression is significantly increased in higher-risk PC patients. Based on these findings, we suggest the CENPF may be an important regulator of PC metabolism through its role in the mitochondria.