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USP22 positively modulates ERα action via its deubiquitinase activity in breast cancer.

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.

SUBMITTER: Wang S

PROVIDER: S-EPMC7560726 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMany cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT).MethodsHuman non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples.ResultsOur data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples.ConclusionsHere, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT. Video abstract.

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USP22 positively modulates ERα action via its deubiquitinase activity in breast cancer.

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