Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha

Abstract

Breast cancer (BC) is the most common neoplastic and lethal malignancy in women. Although antiendocrine therapy is the main treatment for estrogen receptor alpha (ERα)-positive BC, the development of resistance is a major clinical complication. In this study, we aimed to explore the role of ubiquitin-specific peptidase 8 (USP8) in ERα signaling and identify potential targets for endocrine resistance. Public databases were used to analyze USP8 expression, prognosis, clinical characteristics, and immune cell infiltration. Immunohistochemistry and western blot assays were used to detect protein levels and ERα signaling. Quantitative reverse transcription-PCR was used to measure ERα target gene expression. The cell counting kit-8, wound-healing, clone formation, and Transwell assays were used to investigate the effects of USP8 depletion or inhibition on cell proliferation, migration, and invasion. An immunofluorescence assay was used for localizing USP8 and ERα, and a protein stability assay was performed for detecting the degradation of ERα protein. The cell cycle and apoptosis were assessed using flow cytometry. USP8 was highly expressed in the luminal subtype of BC and was associated with poor prognosis. The infiltration levels of many immune cells were positively correlated with USP8 expression. Depletion of USP8 dramatically decreased the ERα signaling activity and weakened the proliferation, migration, and invasion capabilities of BC cells. USP8 knockdown markedly induced apoptosis and cell cycle arrest ( G 0 / G 1 ). Colocalization analysis and protein stability assays indicated a probable mechanism by which USP8 regulates ERα. Our study demonstrates that USP8 might be crucial in BC development and may be considered a potential target for treating ER-positive BC malignancies in vitro.

Expression, Prognostic and Immunological Roles of USP8 in kidney renal clear cell carcinoma: An Integrated Analysis

“…USP8 is a member of the USPs subfamily, widely expressed and distributed in human cells and tissues and a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcription cofactor complex [35]. Previous research reported that USP8 was frequently high-expressed and acted as oncogene in multiple cancers [5][6][7]. However, the function of USP8 in KIRC needs to be further investigated.…”

“…Ubiquitin-speci c protease (USP) family is the largest subfamily of the deubiquitylating enzyme (DUB) family. As a member of USP family, USP8 plays an important role in cell proliferation, migration, invasion and it also regulates protein levels, and the depletion of USP8 stimulates cell cycle arrest and apoptosis [5]. There is increasing evidence suggests that abnormal expression of USP8 can affect diverse signaling pathways in different types of tumors and lead to cancer progression, metastasis, and low survival rate [6][7].…”

Disulfidptosis and ferroptosis related genes predict prognosis and personalize treatment for hepatocellular carcinoma

“…Recent studies have underscored that immune infiltration of tumor cells plays a pivotal role in cancer progression and outcomes ( 17 , 18 ). In light of this, leveraging the B-cell specific long non-coding RNA (lncRNA) signature, we employed a suite of algorithms, namely QUANTISEQ ( http://icbi.at/quantiseq ), CIBERSORT ( https://cibersortx.stanford.edu ), XCELL ( https://comphealth.ucsf.edu/app/xcell ), CIBERSORT abs.mode ( https://cibersortx.stanford.edu ), EPIC ( http://epic.gfellerlab.org ), TIMER ( https://cistrome.shinyapps.io/timer ), and MCP-counter ( https://github.com/ebecht/MCPcounter ), to gauge the extent of immune cell infiltration across high- and low-risk groups.…”

Patient-Specific Analysis of Co-expression Networks for Predicting Clinical Outcomes in Breast Cancer

“…Previous research has shown that ER promotes an estrogen-independent, E2F-mediated transcriptional program in human breast cancer cells [32]. Additionally, the G2M checkpoints and mitotic spindle play direct roles in the cell cycle, which can be regulated by estrogen binding and subsequent activation of signaling pathways that promote cell cycle progression [33][34][35]. The remaining two gene sets are also directly associated with estrogen response.…”