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

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 alpha (ESR1/ER alpha) in endometrial cancer cells. Mechanistically, B23 and activator protein-2 gamma (TFAP2C/AP2 gamma) form a complex that acts as a transcriptional repressor of ER alpha. Our results indicate that B23 or AP2 gamma knockdown can restore ER alpha levels and activate ER alpha-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2 gamma knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ER alpha expression. An increased immunohistochemical expression of AP2 gamma is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2 gamma may act in combination to suppress ER alpha expression in endometrial cancer cells. The inhibition of B23 or AP2 gamma can restore ER alpha expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.