15-Deoxy-Δ12,14-prostaglandin J2 inhibits transcriptional activity of estrogen receptor-α via covalent modification of DNA-binding domain

Han Jong Kim, Joon Young Kim, Zhaojing Meng, Hua Wang Li, Fa Liu, Thomas P. Conrads, Terrence R. Burke, Timothy D. Veenstra, William L. Farrar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J 2 (15d-PGJ2) inhibits proliferation of cancer cells, including breast cancers, by peroxisome proliferator-activated receptor-7 (PPARγ)-dependent and PPARγ-independent mechanisms. However, little is known about its effect on the transcriptional activity of estrogen receptor-α (ERα) that plays vital roles in the growth of breast cancers. Here, we show that 15d-PGJ2 inhibits both 17β-estradiol (E2)-dependent and E2-independent ERα transcriptional activity by PPARγ-independent mechanism. In addition, 15d-PGJ2 directly modifies ERα protein via its reactive cyclopentenone moiety, evidenced by incorporation of biotinylated 15d-PGJ 2 into ERα, both in vitro and in vivo. Nanoflow reverse-phase liquid chromatography tandem mass spectrometry analysis identifies two cysteines (Cys227 and Cys240) within the COOH-terminal zinc finger of ERα DNA-binding domain (DBD) as targets for covalent modification by 15d-PGJ2. Gel mobility shift and chromatin immunoprecipitation assays show that 15d-PGJ2 inhibits DNA binding of ERα and subsequent repression of ERα target gene expression, such as pS2 and c-Myc. Therefore, our results suggest that 15d-PGJ2 can block ERα function by covalent modification of cysteine residues within the vulnerable COOH-terminal zinc finger of ERα DBD, resulting in fundamental inhibition of both hormone-dependent and hormone-independent ERα transcriptional activity.

Original languageEnglish
Pages (from-to)2595-2602
Number of pages8
JournalCancer Research
Volume67
Issue number6
DOIs
StatePublished - 15 Mar 2007
Externally publishedYes

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