title: EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1.
abstract: The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1-binding site at -953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell-cycle control via transcriptional complex formation at the cyclin D1 promoter.
authors: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA19107, USA.
authors: Kongming
authors: K
authors: Wu
authors: Zhaoming
authors: Z
authors: Li
authors: Shaoxin
authors: S
authors: Cai
authors: Lifeng
authors: L
authors: Tian
authors: Ke
authors: K
authors: Chen
authors: Jing
authors: J
authors: Wang
authors: Junbo
authors: J
authors: Hu
authors: Ye
authors: Y
authors: Sun
authors: Xue
authors: X
authors: Li
authors: Adam
authors: A
authors: Ertel
authors: Richard G
authors: RG
authors: Pestell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; D018808:Transcription Factor AP-1; D019938:Cyclin D1; C104381:EYA1 protein, human; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases
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