H3K27 acetylation activated-CYP1B1 promotes invasion, migration and radioresistance in gastric cancer via p38 MAPK-mediated fatty acid metabolism.

[INTRODUCTION] Gastric cancer (GC) is the fifth commonest malignant tumor in the world and ranks third in all cancer-related deaths. Patients suffering from advanced GC have poor prognosis due to metastasis and the resistance to radiotherapy. The current study aims to investigate the specific role of cytochrome P450 1B1 (CYP1B1) in the metastasis and radioresistance of GC cells.

[METHODS] RNA expression profiles in the blood samples of GC patients with or without peritoneal metastasis were screened from the gene expression omnibus database. The prognostic value of CYP1B1 was analyzed using Gene Expression Profiling Interactive Analysis and University of ALabama at Birmingham CANcer databases. The mRNA and protein levels were detected by RT-qPCR and Western blot, respectively. Transwell and wound healing assays were applied to measure the invasive and migratory abilities of GC cells. Clonogenic survival assay was conducted to evaluate the radioresistance of GC cells. Chromatin immunoprecipitation and luciferase reporter assays were performed to analyze the H3K27ac enrichment of CYP1B1 promoter. Co-immunoprecipitation assay was conducted to demonstrate the interaction between CYP1B1 and ARNT. In vivo experiments were performed to validate the effect of CYP1B1 silencing on the radioresistance of GC cells in vivo.

[RESULTS] CYP1B1 was significantly upregulated in the blood samples of GC patients with peritoneal metastasis. Both mRNA and protein levels of CYP1B1 were elevated in highly metastatic GC cells. Knockdown of CYP1B1 repressed the invasive and migratory abilities of highly metastatic GC cells and decreased radioresistance. Mechanistically, YY1/p300 transcription complex enhanced the H3K27 acetylation level in CYP1B1 promoter. CYP1B1 interacted with ARNT to activate p38 MAPK pathway. Rescue experiments showed that ARNT overexpression abolished the suppressive effect of CYP1B1 knockdown on the invasion, migration and radioresistance of highly metastatic GC cells. In vivo experiments validated that CYP1B1 silencing reduced the radioresistance of GC cells in vivo.

[CONCLUSION] H3K27ac-induced upregulation of CYP1B1 promoted the invasion, migration and radioresistance of GC cells by facilitating p38 MAPK-mediated fatty acid metabolism. Our findings suggest that CYP1B1 may serve as a therapeutic target to overcome metastasis and radioresistance in GC.