Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition

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...

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Bibliographic Details
Published in:Molecular cancer research 2018-10, Vol.16 (10), p.1530-1542
Main Authors: Molehin, Deborah, Castro-Piedras, Isabel, Sharma, Monica, Sennoune, Souad R, Arena, Daphne, Manna, Pulak R, Pruitt, Kevin
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Aromatase - genetics
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Chromatography, Liquid
Female
Gene Expression Regulation, Neoplastic - drug effects
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - genetics
Humans
Lysine - genetics
MCF-7 Cells
Protein Processing, Post-Translational
Sirtuin 1 - antagonists & inhibitors
Sirtuin 1 - genetics
Tandem Mass Spectrometry
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Summary: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 ( ). 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. 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. .
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.MCR-18-0047