Stabilization of estrogen receptor α by USP37 contributes to the progression of breast cancer

• Published in: Cancer science Vol. 114; no. 5; pp. 2041 - 2052
• Main Authors: Cao, Jing, Wang, Xiaobo, Wang, Shouman, Chen, Zihua, Tang, Jianing
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc
• Subjects: Breast - pathology; Breast cancer; Breast Neoplasms - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cloning; deubiquitylation; Endocrine therapy; Endopeptidases - metabolism; Enzymes; Epidermal growth factor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; estrogen receptor α (ERα); Estrogen receptors; Estrogens; Female; Flow cytometry; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Ligands; MCF-7 Cells; Medical prognosis; Morbidity; Original; ORIGINAL ARTICLES; Ovaries; Phase transitions; Plasmids; Post-translation; Proteins; stabilization; Ubiquitination; USP37; breast cancer; USP37; stabilization; estrogen receptor α (ERα); deubiquitylation
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15613

Breast cancer is a major cause of cancer‐related morbidity and mortality in women. Estrogen receptor‐positive breast cancer accounts for roughly 70%‐80% of breast tumors, and estrogen receptor alpha (ERα) has been considered as a key driver in promoting breast cancer progression. In the present study, we identified USP37 as a novel modulator in modulating ERα ubiquitination and stability. The expression of USP37 was upregulated in ERα‐positive breast cancer and correlated with ERα protein level. High expression of USP37 was associated with unfavorable prognosis. USP37 depletion resulted in significantly decreased ERα protein level, ERα target genes expression as well as the estrogen response element activity in breast cancer cells. Further mechanistic study revealed the interaction between USP37 and ERα: USP37 regulated ERα signaling through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48‐specific polyubiquitination process. Additionally, USP37 depletion led to growth inhibition and cell cycle arrest of ERα‐positive breast cancer cells, which could be further rescued by ERα overexpression. Overall, our study proposed a novel post‐translational mechanism of ERα in promoting breast cancer progression. Targeting USP37 may be proved to be a promising strategy for patients with ERα‐positive breast cancer. USP37 regulated ERα signaling in breast cancer through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48‐specific poly‐ubiquitination process. Targeting USP37 may be proved to be a promising strategy for patients with ERα‐positive breast cancer.