TY - JOUR
T1 - Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERβ and KLF5
AU - Nakajima, Yuka
AU - Akaogi, Kensuke
AU - Suzuki, Takashi
AU - Osakabe, Asami
AU - Yamaguchi, Chie
AU - Sunahara, Nanae
AU - Ishida, Junji
AU - Kako, Koichiro
AU - Ogawa, Sonoko
AU - Fujimura, Tetsuya
AU - Homma, Yukio
AU - Fukamizu, Akiyoshi
AU - Murayama, Akiko
AU - Kimura, Keiji
AU - Inoue, Satoshi
AU - Yanagisawa, Junn
PY - 2011/4/12
Y1 - 2011/4/12
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.2001551
DO - 10.1126/scisignal.2001551
M3 - Article
C2 - 21487105
AN - SCOPUS:79954557105
VL - 4
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 168
M1 - ra22
ER -