Identifying Dysregulated Epigenetic Enzyme Activity in Castrate-Resistant Prostate Cancer Development.

Abstract

There is a tremendous need for novel strategies aimed at directly assessing activities of histone modifiers to probe epigenetic determinants associated with disease progression. Here, we developed a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in prostate cancer (PCa). This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant (CR) PCa cell line compared to its hormone-sensitive (HS) isogenic counterpart. NAD+-dependent deacetylation assays revealed down-regulated sirtuin activity in validated CR lines. Levels of acetyltransferases GCN5, PCAF, CBP, and p300 were unchanged between matched HS and CR cell lines. However, autoacetylation of p300 at K1499, a modification known to enhance HAT activity and a target of deacetylation by SIRT2, was highly elevated in CR cells, while SIRT2 protein level was reduced in CR cells. Interrogation of HS and matched CR xenograft lines reveals that H3K18 hyperacetylation, increased p300 activity, and decreased SIRT2 expression are associated with progression to CR in 8/12 (66%). Tissue microarray analysis revealed that hyperacetylation of H3K18 is a feature of CRPC. Inhibition of p300 results in lower H3K18ac levels and increased expression of androgen receptors. Thus, a novel histone array identifies altered enzyme activities during the progression to CRPC and may be utilized in a personalized medicine approach. Reduced SIRT2 expression and increased p300 activity lead to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC.

• Authors: Jin-Hee Lee, Bing Yang, Anastasia J Lindahl, Nathan Damaschke, Melissa D Boersma, Wei Huang, Eva Corey, David F Jarrard, John M Denu
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 12 Issue 11 Pg. 2804-2814 (11 17 2017) ISSN: 1554-8937 [Electronic] United States
• PMID: 28949514 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Histones
• Histone Acetyltransferases
• SIRT2 protein, human
• Sirtuin 2
• Sirtuins

Topics

• Acetylation
• Animals
• Cell Line, Tumor
• Enzyme Activation
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Histone Acetyltransferases (metabolism)
• Histones (genetics, metabolism)
• Humans
• Male
• Mice
• Orchiectomy
• Prostatic Neoplasms (enzymology, genetics, metabolism)
• Protein Array Analysis
• Sirtuin 2 (metabolism)
• Sirtuins (metabolism)
• Xenopus