Impact of SETD8/KMT5A Overexpression on Hepatocellular Carcinoma Progression and Prognosis

BackgroundHepatocellular carcinoma (HCC) has a poor prognosis due to its high recurrence rate, even after curative surgery. Epigenetic regulators play a critical role in cancer progression, and the histone methyltransferase SETD8/KMT5A has been reported to be overexpressed in various malignancies. This study aimed to elucidate the role of SETD8/KMT5A in HCC. MethodsWe investigated SETD8/KMT5A expression in 345 primary HCC resection specimens through immunohistochemical staining. For functional analyses, we conducted loss-of-function study of SETD8/KMT5A using HCC cell lines, including in vitro assays for proliferation, cell cycle, invasion, and RNA sequencing with gene ontology (GO) analysis. Additionally, we performed xenograft experiments in mice and performed similar experiments using the SETD8/KMT5A inhibitor UNC0379. ResultsAll cases were divided into either the SETD8 high-expression (n=197) or low-expression (n=148) groups. The high-expression group exhibited significantly poorer 5-year overall survival and 2-/5-year disease-free survival compared with the low-expression group (both p<0.001). Multivariate analysis indicated that high SETD8 expression was an independent poor prognosis factor in overall (p=0.0255) and disease-free (p=0.0051) survival. SETD8/KMT5A knockdown suppressed proliferation by inhibition of G1 to S phase transition (p<0.001). GO terms were related to cancer progression, including cell adhesion, MAPK-related signaling and chromatin remodeling. SETD8/KMT5A knockout using CRISPR/Cas9 inhibited tumor growth (p<0.01) in vivo. ConclusionsSETD8/KMT5A overexpression was associated with poor prognosis and was an independent prognostic factor in HCC. In vitro and in vivo analysis, the inhibition of SETD8 could repress HCC progression through the regulation of cell activity and cell cycle transition.