2025/01/28 by Lie Yuan, Yongqing Cai, Gang Wang +7 · 1 citation
Biochemistry, Genetics and Molecular Biology · #Estrogen and related hormone effects #Wnt/β-catenin signaling in development and cancer #Genomics and Chromatin Dynamics
paper · doi:10.1111/bph.17453
BACKGROUND AND PURPOSE: Breast cancer is a leading threat to women's health, with approximately 70% of cases being estrogen receptor-positive. SGK3 is regulated by estrogen and is positively associated with estrogen receptor expression, although its molecular role remains unclear. EXPERIMENTAL APPROACH: Proteomics was used to identify SGK3's downstream targets. Tissue microarray immunofluorescence evaluated SGK3 and ZMIZ2 expression in ER+ breast cancer. Lentiviral-mediated knockdown and overexpression of SGK3 and/or ZMIZ2 assessed their effects on cell proliferation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analyzed p-STAT3 binding to the ZMIZ2 promoter, and Co-immunoprecipitation (Co-IP) examined ZMIZ2-β-catenin interaction. KEY RESULTS: SGK3 expression was elevated in breast tumour tissues correlating with reduced patient survival. Proteomic analysis identified ZMIZ2 as a downstream target of SGK3. Overexpression of SGK3 promoted the proliferation of estrogen receptor-positive breast cancer in MCF-7 and T47D cells. Inhibition had the opposite effects. ZMIZ2 overexpression rescued the proliferation deficit in SGK3 knockdown cells. ZMIZ2 was found to bind and stabilises β-catenin. Knockdown of SGK3 led to β-catenin degradation via polyubiquitination, a process reversed by ZMIZ2 overexpression. STAT3 was identified as a downstream effector of SGK3 and its knockdown reduced cytoplasmic and nuclear p-STAT3 and STAT3, and inhibited ZMIZ2 and β-catenin expression. Celastrol suppressed estrogen receptor-positive breast cancer cell proliferation by inhibiting the SGK3/STAT3/ZMIZ2/β-catenin pathway. CONCLUSIONS AND IMPLICATIONS: SGK3 expression is associated with poorer survival rates, thus SGK3 is a potential therapeutic target. As celastrol can inhibit SGK3 expression it could be an effective therapeutic agent.