Estrogen Regulates Tumor Growth Through a Nonclassical Pathway that Includes the Transcription Factors ERβ and KLF5

被引：89

作者：

Nakajima, Yuka ^{[1
,2
]}

Akaogi, Kensuke ^{[1
]}

Suzuki, Takashi ^{[3
]}

Osakabe, Asami ^{[1
]}

Yamaguchi, Chie ^{[1
]}

Sunahara, Nanae ^{[1
]}

Ishida, Junji ^{[2
]}

Kako, Koichiro ^{[2
]}

Ogawa, Sonoko ^{[4
]}

Fujimura, Tetsuya ^{[5
]}

Homma, Yukio ^{[5
]}

Fukamizu, Akiyoshi ^{[2
]}

Murayama, Akiko ^{[1
,2
,6
]}

Kimura, Keiji ^{[1
]}

Inoue, Satoshi ^{[7
,8
]}

Yanagisawa, Junn ^{[1
,2
]}

机构：

[1] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058577, Japan

[2] Univ Tsukuba, Life Sci Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058577, Japan

[3] Tohoku Univ, Grad Sch Med, Dept Pathol & Histotechnol, Sendai, Miyagi 9808575, Japan

[4] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan

[5] Univ Tokyo, Grad Sch Med, Dept Urol, Bunkyo Ku, Tokyo 1138655, Japan

[6] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol, Kawasaki, Saitama 3510198, Japan

[7] Univ Tokyo, Grad Sch Med, Dept Geriatr Med, Bunkyo Ku, Tokyo 1138655, Japan

[8] Univ Tokyo, Grad Sch Med, Dept Antiaging Med, Bunkyo Ku, Tokyo 1138655, Japan

来源：

SCIENCE SIGNALING | 2011年 / 4卷 / 168期

关键词：

KRUPPEL-LIKE FACTOR-5; PROSTATE-CANCER CELLS; RECEPTOR-BETA; EPITHELIAL-CELLS; BREAST-CANCER; DIFFERENTIAL EXPRESSION; ANDROGEN RECEPTOR; FOXO PROTEINS; PROLIFERATION; TARGET;

D O I：

10.1126/scisignal.2001551

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Clinical evidence suggests that antiestrogens inhibit the development of androgen-insensitive prostate cancer. Here, we show that the estrogen receptor beta (ER beta) mediates inhibition by the antiestrogen ICI 182,780 (ICI) and its enhancement by estrogen. ER beta associated with gene promoters through the tumor-suppressing transcription factor KLF5 (Kruppel-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 ER beta 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 ER beta, 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 ER beta positively correlated with longer cancer-specific survival in prostate cancer patients. Our results demonstrate that estrogens and antiestrogens affect prostate tumor growth through ER beta-mediated regulation of KLF5.

引用

页数：12

共 65 条

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