Prognostic impact of SET domain-containing protein 8 and protein arginine methyltransferase 5 in patients with hepatocellular carcinoma following curative resection

Histone methyltransferases are important determinants of the initiation and progression of hepatocellular carcinoma (HCC) and represent promising therapeutic targets. However, whether the expression profile of multiple histone methyltransferases represents a poorer prognosis is entirely unknown. The aim of the present study was to investigate the association between histone methylation and HCC phenotype, and the prognostic value of combining expression levels of SET domain-containing protein 8 (SET8) with protein arginine methyltransferase 5 (PRMT5) in patients with HCC following curative resection. The retrospective study included 195 consecutive patients who had undergone hepatectomy for HCC. Immunohistochemical staining for SET8 and PRMT5 was performed on paraffin-embedded tumor tissue microarrays. Expression was analyzed for correlations with clinicopathological features, marker co-expression and patients' survival by univariate and multivariate analyses. Positive SET8 expression was noted in 104 patients (53.3%), and was associated with PRMT5 expression (n=106, 54.4%, P<0.05). Immunohistochemical analysis demonstrated that high expression of SET8 and PRMT5 was significantly associated with poor overall survival (OS, P<0.001) and time to recurrence (TTR, P<0.001). Multivariate Cox analysis revealed that SET8 and PRMT5, along with vascular invasion, tumor size and tumor number, were independent prognostic factors for OS and TTR. The combination of SET8 and PRMT5 demonstrated an improved capacity to predict patient mortality and disease recurrence (P=0.002 and P=0.004, respectively), particularly for the prediction of early recurrence (P<0.001). In conclusion, high expression of SET8 combined with PRMT5 was associated with a high rate of recurrence and poor survival in patients with HCC. The independent pattern of histone methylation represents a novel insight into tumor progression and therapeutic targets for HCC.