title: Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERβ and KLF5.
abstract: Clinical evidence suggests that antiestrogens inhibit the development of androgen-insensitive prostate cancer. Here, we show that the estrogen receptor β (ERβ) mediates inhibition by the antiestrogen ICI 182,780 (ICI) and its enhancement by estrogen. ERβ associated with gene promoters through the tumor-suppressing transcription factor KLF5 (Krüppel-like zinc finger transcription factor 5). ICI treatment increased the recruitment of the transcription coactivator CBP [CREB (adenosine 3',5'-monophosphate response element-binding protein)-binding protein] to the promoter of FOXO1 through ERβ and KLF5, which enhanced the transcription of FOXO1. The increase in FOXO1 abundance led to anoikis in prostate cancer cells, thereby suppressing tumor growth. In contrast, estrogen induced the formation of complexes containing ERβ, KLF5, and the ubiquitin ligase WWP1 (WW domain containing E3 ubiquitin protein ligase 1), resulting in the ubiquitination and degradation of KLF5. The combined presence of KLF5 and ERβ positively correlated with longer cancer-specific survival in prostate cancer patients. Our results demonstrate that estrogens and antiestrogens affect prostate tumor growth through ERβ-mediated regulation of KLF5.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Kensuke
authors.initials: K
authors.lastname: Akaogi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Asami
authors.initials: A
authors.lastname: Osakabe
authors.forename: Chie
authors.initials: C
authors.lastname: Yamaguchi
authors.forename: Nanae
authors.initials: N
authors.lastname: Sunahara
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kako
authors.forename: Sonoko
authors.initials: S
authors.lastname: Ogawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fujimura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Akiko
authors.initials: A
authors.lastname: Murayama
authors.forename: Keiji
authors.initials: K
authors.lastname: Kimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D000368:Aged; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047629:Estrogen Receptor beta; D004967:Estrogens; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D000077267:Fulvestrant; D004958:Estradiol; D050882:CREB-Binding Protein