Nucleophosmin/B23 is a negative regulator of estrogen receptor α expression via AP2γ in endometrial cancer cells

// Chiao-Yun Lin 1, 2, * , Angel Chao 1, 2, 3, * , Tzu-Hao Wang 1, 2, 3, * , Li-Yu Lee 4 , Lan-Yan Yang 5 , Chia-Lung Tsai 3 , Hsin-Shih Wang 1, 6 , Chyong-Huey Lai 1, 2 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan 2 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 3 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taiwan 4 Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan 5 Statistics, Clinical Trial Center, Chang Gung Memorial Hospital, Taipei City, Taiwan 6 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan * These authors contribute equally to this work Correspondence to: Hsin-Shih Wang, email: hswang@cgmh.org.tw Chyong-Huey Lai, email: sh46erry@ms6.hinet.net Keywords: endometrial cancer, nucleophosmin, estrogen receptor α, activator protein-2γ, hormonal therapy Received: February 29, 2016      Accepted: July 18, 2016      Published: August 04, 2016 ABSTRACT 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.