Estrogen receptor α (ERα) is the crucial factor in ERα-positive breast cancer progression. Endocrine therapies targeting ERα signaling is one of the widely used therapeutic strategies for breast cancer. However, a large number of the patients become refractory to therapy. Abnormal expression of ERα co-regulator facilitates breast cancer development and tendency of endocrine resistance. Thus, it is necessary to discover the novel co-regulators modulating ERα action. Here, we demonstrate that histone deubiquitinase USP22 is highly expressed in breast cancer samples compared with that in the benign tissue, and high expression of USP22 was significantly associated with poorer overall survival in BCa samples. Moreover, USP22 associates with ERα to be involved in maintenance of ERα stability. USP22 enhances ERα-induced transactivation. We further provide the evidence that USP22 is recruited together with ERα to cis-regulatory elements of ERα target gene. USP22 promotes cell growth even under hypoxia condition and with the treatment of ERα antagonist in breast cancer cells. Importantly, the deubiquitination activity of USP22 is required for its functions on maintenance of ERα stability, thereby enhancing ERα action and conferring endocrine resistance in breast cancer.

雌激素受体α（ERα）是ERα阳性乳腺癌进展的关键因素。针对 ERα 信号的内分泌疗法是广泛使用的乳腺癌治疗策略之一。然而，大量患者变得难以治疗。ERα 共调节因子的异常表达促进了乳腺癌的发展和内分泌抵抗的趋势。因此，有必要发现调节 ERα 作用的新型协同调节剂。在这里，我们证明组蛋白去泛素化酶 USP22 在乳腺癌样本中比在良性组织中高表达，并且 USP22 的高表达与 BCa 样本中较差的总体存活率显着相关。此外，USP22 与 ERα 相关联，参与维持 ERα 的稳定性。USP22 增强 ERα 诱导的反式激活。ERα 靶基因的顺式调控元件。USP22 即使在缺氧条件下和 ERα 拮抗剂治疗乳腺癌细胞时也能促进细胞生长。重要的是，USP22 的去泛素化活性是维持 ERα 稳定性的功能所必需的，从而增强 ERα 作用并赋予乳腺癌内分泌抵抗。