FAM60A Regulates SIN3A–HDAC Complex Activity to Induce G1/S Phase Arrest and Promote Differentiation of Low‐Grade Glioma

BACKGROUND: Low-grade gliomas (LGGs) exhibit dysregulated cell-cycle progression, contributing to tumor growth. Family with sequence similarity 60 member A (FAM60A), a component of the SIN3A-HDAC epigenetic complex, is implicated in cell proliferation and stemness, but its role in glioma remains unclear. METHODS: Human glioblastoma U87 MG cells and SW1088 (grade III astrocytoma) were used to investigate the function of FAM60A. Serum starvation was applied to synchronize cells in the G1 phase. Cellular proliferation, migration, and invasion capacities were examined using the CCK-8 and Transwell assays. The distribution of cells within various phases of the cell cycle was assessed through flow cytometry. HDAC activity, histone acetylation, and protein interactions were examined by fluorometric assay, Western blotting, and co-immunoprecipitation. Rescue experiments with the HDAC inhibitor were used to evaluate functional interplay among FAM60A, SIN3A, and HDAC. RESULTS: FAM60A depletion inhibited proliferation, induced G1/S arrest, downregulated Cyclin D1/CDK4/6, and upregulated p21/p27, while reducing migration and stemness. Overexpression had opposite effects. Mechanistically, FAM60A promoted the expression and activity of the SIN3A-HDAC complex, thereby reducing histone acetylation and facilitating the transcriptional repression of cell-cycle inhibitors. SIN3A knockdown or HDAC inhibition recapitulated FAM60A loss, and their combination further enhanced G1 arrest, cell-cycle inhibitor upregulation, histone acetylation, and differentiation. CONCLUSION: FAM60A promotes LGG cell proliferation by facilitating SIN3A-HDAC-mediated transcriptional repression of cell-cycle inhibitors. Targeting FAM60A or the SIN3A-HDAC complex may represent a potential therapeutic strategy for controlling LGG growth.