H3K27me3 Modified FBXO10 Promotes Golgi Stress to Accelerate Traumatic Brain Injury via Activation of the RAS / ERK Axis

Traumatic brain injury (TBI) is a type of brain disease that causes disability and a high mortality rate, affecting patient health. Our study aimed to explore the mechanism of F‐box protein 10 (FBXO10) in neuronal apoptosis and Golgi stress. Cell viability was detected by cell counting kit‐8 (CCK‐8). Lactate dehydrogenase (LDH), interleukin‐1β (IL‐1β), and tumor necrosis factor‐alpha (TNF‐α) levels were measured by commercial kit or enzyme linked immunosorbent assay (ELISA). Apoptosis was assayed by flow cytometry. Immunofluorescence and Western blot were used to detect Rat sarcoma (RAS), total‐Extracellular signal‐regulated kinase (ERK)1/2, phospho‐ERK1/2, and Golgi stress marker proteins (GM130, GOLPH3, and Golgin97) expression. The FBXO10‐RAS interaction and RAS ubiquitination were assessed by co‐immunoprecipitation. Trimethylation of Lys‐27 in histone 3 (H3K27me3) modification level on FBXO10 promoter was analyzed by chromatin immunoprecipitation (ChIP). Knockdown of RAS suppressed Golgi stress and apoptosis in H 2 O 2 ‐treated HT‐22 and NSC34 cells by inactivating the RAS/ERK axis. FBXO10 suppressed Golgi stress and apoptosis in H 2 O 2 ‐induced neuronal cells. Furthermore, FBXO10 inhibited Golgi stress and apoptosis by inactivating the RAS/ERK axis. Mechanistically, the upregulated enhancer of zeste homolog 2 (EZH2) repressed FBXO10 expression by promoting H3K27me3 modification in the FBXO10 promoter region, and FBXO10 promoted the degradation of RAS in an ubiquitin‐dependent manner. Moreover, EZH2 activated the RAS/ERK axis by downregulating FBXO10 expression to promote Golgi stress and apoptosis in H 2 O 2 ‐treated HT‐22 and NSC34 cells. EZH2‐mediated H3K27me3 modification promoted Golgi stress and apoptosis in neuronal by activating the RAS/ERK axis via inhibition of FBXO10 expression. Our study provided the theoretical basis and potential clinical targets for TBI treatment.