Abstract
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.
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Acknowledgements
We appreciate Dr Yanshu Li, Dr Yunlong Huo, and Dr Tao Wen for helpful technique support. We thank Dr Shigeaki Kato (Soma Central Hospital, Fukushima, Japan) for providing ERα, its truncated mutants, and pERE-tk-luc plasmids, as well as important comments for draft. We thank Dr Yujie Sun (Nanjing Medical University, Nanjing, China) for MCF-7, T47D, BT474, and MDA-MB-231 cells, which were purchased from American Type Culture Collection.
Funding
This study was supported by the National Natural Science Foundation of China (31871286 for YZ, 81872015 for CW, 31701102 for SW, 81702800 for RZ, and 81502438 for TZ); 973 Program Grant from the Ministry of Science and Technology of China (2013CB945201); Ministry of Education fund innovation team (IRT 13101); Foundation for Special Professor of Liaoning Province for YZ (the fifth batch).
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Wang, S., Zhong, X., Wang, C. et al. USP22 positively modulates ERα action via its deubiquitinase activity in breast cancer. Cell Death Differ 27, 3131–3145 (2020). https://doi.org/10.1038/s41418-020-0568-2
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DOI: https://doi.org/10.1038/s41418-020-0568-2
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