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Ada3 Requirement for HAT Recruitment to Estrogen Receptors and Estrogen-Dependent Breast Cancer Cell Proliferation

Divisions of ¹ Cancer Biology and ² Molecular Oncology, Evanston Northwestern Healthcare Research Institute; ³ Department of Medicine, Feinberg School of Medicine; ⁴ Department of Biochemistry, Molecular Biology and Cell Biology, Weinberg College of Arts, Northwestern University, Evanston, Illinois

Requests for reprints: Vimla Band, Department of Genetics, Cell Biology & Anatomy, 985805 Nebraska Medical Center, Omaha, NE 68198-5805. Phone: 402-559-8565; Fax: 402-559-7328; E-mail: vband{at}unmc.edu.

We have previously shown that evolutionarily conserved alteration/deficiency in activation (Ada) protein associates with and promotes estrogen receptor (ER)–mediated target gene expression. Here, we examined the role of endogenous Ada3 to recruit histone acetyl transferases (HAT) to an ER-responsive promoter and its role in estrogen-dependent cell proliferation and malignant phenotype. Using a combination of glycerol gradient cosedimentation and immunoprecipitation analyses, we show that Ada3, ER, and three distinct HATs [p300, (p300/CBP-associated factor) PCAF, and general control nonrepressed 5 (Gcn5)] are present in a complex. Using chromatin immunoprecipitation analysis, we show that short hairpin RNA (shRNA)–mediated knockdown of Ada3 in ER-positive breast cancer cells significantly reduced the ligand-dependent recruitment of p300, PCAF, and Gcn5 to the ER-responsive pS2 promoter. Finally, we use shRNA knockdown to show that Ada3 is critical for estrogen-dependent proliferation of ER-positive breast cancer cell lines in two-dimensional, as well as three-dimensional, culture. Knockdown of Ada3 in ER-positive MCF-7 cells induced reversion of the transformed phenotype in three-dimensional culture. Thus, our results show an important role of Ada3 in HAT recruitment to estrogen-responsive target gene promoters and for estrogen-dependent proliferation of breast cancer cells. [Cancer Res 2007;67(24):11789–97]

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				Correction: Ada3 Requirement for ER-Dependent Cell Proliferation Cancer Res., March 1, 2008; 68(5): 1609 - 1609. [Full Text] [PDF]