Nucleophosmin/B23 is a negative regulator of estrogen receptor α expression via AP2γ in endometrial cancer cells
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Chiao-Yun Lin1,2,*, Angel Chao1,2,3,*, Tzu-Hao Wang1,2,3,*, Li-Yu Lee4, Lan-Yan Yang5, Chia-Lung Tsai3, Hsin-Shih Wang1,6, Chyong-Huey Lai1,2
1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan
2Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
3Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taiwan
4Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan
5Statistics, Clinical Trial Center, Chang Gung Memorial Hospital, Taipei City, Taiwan
6Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
*These authors contribute equally to this work
Hsin-Shih Wang, email: [email protected]
Chyong-Huey Lai, email: [email protected]
Keywords: endometrial cancer, nucleophosmin, estrogen receptor α, activator protein-2γ, hormonal therapy
Received: February 29, 2016 Accepted: July 18, 2016 Published: August 04, 2016
Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/B23) suppression can restore the expression of estrogen receptor α (ESR1/ERα) in endometrial cancer cells. Mechanistically, B23 and activator protein-2γ (TFAP2C/AP2γ) form a complex that acts as a transcriptional repressor of ERα. Our results indicate that B23 or AP2γ knockdown can restore ERα levels and activate ERα-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2γ knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. An increased immunohistochemical expression of AP2γ is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2γ may act in combination to suppress ERα expression in endometrial cancer cells. The inhibition of B23 or AP2γ can restore ERα expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.
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