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.
Highlights
Endometrial cancer is the most common cancer of the female reproductive tract in industrialized countries [1]
We demonstrate for the first time that nucleophosmin (NPM1/ B23) suppression can restore the expression of estrogen receptor a (ESR1/ERa) in endometrial cancer cells
ERα expression is reduced in high-passage RL95-2 and Ishikawa endometrial cancer cells
Summary
Endometrial cancer is the most common cancer of the female reproductive tract in industrialized countries [1]. The disappearance of steroid hormone receptor expression is common in patients with recurrent estrogen-related cancers, hampering the clinical utility of hormonal therapy [8, 9]. The expression of estrogen receptor 1 (ESR1/ERα, gene ID 2099) is tightly regulated in a coordinated fashion by numerous transcription factors, including retinoic acid receptor-α (RARα), PAX2, GATA3, NKX3.1, LEF1, FOXA1, and activator protein-2γ (TFAP2C/AP2γ, gene ID 7022) [10,11,12,13,14,15,16]. AP2 proteins consist of homo - and heterodimers that bind to GC-rich DNA sequences and are able to either www.impactjournals.com/oncotarget activate or repress target genes [18]. AP2 can contribute to tumorigenesis by regulating the expression of specific target genes involved in growth control, including ER [19], HER2 [20], and CDKN1A [21]
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