Usp22 Positively Modulates Er Alpha Action Via Its Deubiquitinase Activity In Breast Cancer

Estrogen receptor alpha (ER alpha) is the crucial factor in ER alpha-positive breast cancer progression. Endocrine therapies targeting ER alpha 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 ER alpha co-regulator facilitates breast cancer development and tendency of endocrine resistance. Thus, it is necessary to discover the novel co-regulators modulating ER alpha 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 ER alpha to be involved in maintenance of ER alpha stability. USP22 enhances ER alpha-induced transactivation. We further provide the evidence that USP22 is recruited together with ER alpha to cis-regulatory elements of ER alpha target gene. USP22 promotes cell growth even under hypoxia condition and with the treatment of ER alpha antagonist in breast cancer cells. Importantly, the deubiquitination activity of USP22 is required for its functions on maintenance of ER alpha stability, thereby enhancing ER alpha action and conferring endocrine resistance in breast cancer.