Sorting nexin 10 promotes triple-negative breast cancer progression through modulating cholesterol biosynthesis via stabilizing SREBP2

Abstract

ABSTRACT Objective Triple-negative breast cancer (TNBC) lacks effective therapeutics in clinical practice. Sorting nexin 10 (SNX10) plays essential roles in various cancers, and the role of SNX10 in TNBC remains unknown. This study investigated the role and action mechanism of SNX10 in TNBC. Methods Using the Kaplan–Meier Plotter database and bc-GenExMiner database to analyze the SNX10 expression and clinical significance. Functional assays, including MTT, colony formation, transwell assays, and xenograft experiments, were used to evaluate the role of SNX10 in TNBC. The GeneChip PrimeView Human Gene Expression Array was used to determine the downstream targets and pathways. Cholesterol levels and the expression of enriched cholesterol synthesis genes were detected by Filipin assay, RT-PCR, and Western Blot. The relationship of SNX10 and cholesterol biosynthesis was confirmed using CO-IP and immunofluorescence staining assays. Results SNX10 is positively related to poor prognosis of breast cancer and markedly up-regulated in TNBC. Knockdown of SNX10 suppressed cell proliferation, migration, and invasion, and slowed the tumor growth in vivo. Mechanistically, SNX10 positively regulates the content and distribution of cellular cholesterol, as does the expression of enriched cholesterol synthesis genes, and SNX10 interacts with SREBP2 and prolongs its half-life. Blocking with lovastatin, cholesterol, or siSREBP2 reversed these effects caused by altering SNX10 in TNBC cells in vitro. Conclusion SNX10 promoted TNBC progression through the regulation of cholesterol biosynthesis, which was mediated by interaction with SREBP2 and maintenance of its stability. SNX10 may be an effective therapeutic target for TNBC, and our study provides new insights into therapeutic strategies.