Format

Send to

Choose Destination
Mol Cancer Res. 2018 Oct;16(10):1530-1542. doi: 10.1158/1541-7786.MCR-18-0047. Epub 2018 Jun 19.

Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition.

Author information

1
Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, Texas.
2
Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, Texas.
3
Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, Texas. kevin.pruitt@ttuhsc.edu.

Abstract

Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. However, advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (CYP19A1). Yet, despite aromatase being a primary target for breast cancer therapy, its posttranslational regulation has been virtually unexplored. Acetylation is a posttranslational modification (PTM) known to alter the activity and stability of many oncoproteins, and given the role of KDIs in regulating aromatase expression, we postulate that aromatase acetylation acts as a novel posttranslational regulatory mechanism that impacts aromatase expression and/or activity in breast cancer. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that aromatase is basally acetylated on several lysine residues (108, 169, 242, 262, 334, 352, and 354) in MCF-7 cells, and treatment with a SIRT-1 inhibitor induced additional acetylation (376, 390, 440, and 448). These acetylated lysine residues are in regions critical for aromatase activity. Site-directed mutagenesis and overexpression studies demonstrated that K108R/Q or K440R/Q mutations significantly altered aromatase activity in breast cancer cells without altering its subcellular localization.Implications: These findings demonstrate a novel posttranslational regulation of aromatase and uncover novel anticancer effects of deacetylase inhibitors, thus providing new insight for ongoing development of deacetylase inhibitors as cancer therapeutics. Mol Cancer Res; 16(10); 1530-42. ©2018 AACR.

PMID:
29921733
DOI:
10.1158/1541-7786.MCR-18-0047
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center