C/EBPβ Sustains A Gene Expression Program That Promotes Tumor Growth Of Ovarian Cancer Cells

Background: Ovarian cancer is the primary cause of fatality from gynecological malignancies,which is characterized by genomically instability and intra-tumor heterogeneity,making it generally a refractory disease.Identifying effective targets is the urgent demand for improving the dismal outcome of this disease.C/EBPβ can recruit the methyltransferase DOT1 L of H3K79 methylation and maintain an open chromatin state to promote gene transcription including DNA repair signaling,cisplatin-resistance genes and survival signals,which indicates C/EBPβ acts as a ‘master regulator’ in ovarian malignancy.Objective: This study is to investigate the pro-proliferative roles of C/EBPβ in ovarian cancer and the relative mechanisms.Methods: Clinical samples were used to explore the relationship between C/EBPβexpression and tumor proliferation.The effects of C/EBPβ on tumor growth were evaluated by colony formation and cell proliferation assay in vitro,and orthotopic xenograft model of ovarian cancer in vivo.RNA-sequencing combined with chromatin immunoprecipitation(Ch IP)sequencing were used to identify C/EBPβ target genes.A comprehensive investigation of the RNA-sequencing,C/EBPβ Ch IP-sequencing and gene expression meta-analysis was performed to identify genes associated with C/EBPβ and prognosis of patients with ovarian cancer.Phospho-antibody array was used to clarify the molecular mechanisms of C/EBPβ in promoting tumor growth.Gene expression levels and activity of signaling pathways were measured by quantitative real time polymerase chain reaction(q PCR)or immunoblotting.Results: Here we found that high expression of C/EBPβ was associated with proliferation and C/EBPβ promoted tumor growth in ovarian cancer.A large number of genes targeted and upregulated by C/EBPβ were associated with poor prognosis of patients with ovarian cancer and functioned in the promotional effect of C/EBPβ on tumor growth.By directly targeting and upregulating MICAL2,C/EBPβ triggered a MAPK-dominated signal cascade that coordinated to promote cell proliferation.Conclusions: These findings reveal C/EBPβ as a ‘master regulator’ in regulating cell proliferation,and suggest that C/EBPβ may be a valuable target for the therapy of ovarian cancer.