Abstract
AbsractBackgroundTumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown.MethodsThe effect of SMYD3 on invasiveness and metastasis of HCC was analyzed by immunohistochemistry, migration assay, invasion assay, wound healing assay and in vivo lung metastasis assay. Mass spectrometry analysis was conducted using proteins pulled down by H3K4me3 antibody in SMYD3-overexpressing cells. Luciferase reporter, chromatin immunoprecipitation, Electrophoretic mobility shift assay were used to measure the regulation of SLUG transcription by SMYD3-ANKHD1. In addition, the role of SMYD3-ANKHD1 in determining clinical outcomes for HCC patients was investigated by immunohistochemistry in 243 HCC tissues.ResultsSMYD3 was an independent prognostic factor of HCC and promoted migration and invasion of human HCC cells. ANKHD1 was identified by mass spectrometry as a co-regulator with SMYD3. ANKHD1 interacted with H3K4me3 when cells were overexpressing SMYD3. The pro-migratory and pro-invasive effects of SMYD3 were attenuated when ANKHD1 was knocked down by siRNA. Furthermore, we found that SMYD3 bound and activated the SLUG gene promoter in a manner associated with elevating H3K4me3, H3K9Ac and H3K14Ac. Knockdown of ANKHD1 could attenuate the SMYD3-dependent activation of Slug expression. We further detected the expression of SMYD3 and ANKHD1 in 243 HCC patients and found that patients with positive coexpression of SMYD3 and ANKHD1 (SMYD3+ANKHD1+) had the shortest overall and recurrence-free survival.ConclusionOur findings provide a novel molecular mechanism for the SMYD3-regulated HCC migration and metastasis, and indicates that SMYD3-ANKHD1 may be a potential target for treating HCC.
Highlights
Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection
We found that SET and MYND domain-containing protein 3 (SMYD3) bound and activated the SLUG gene promoter in a manner associated with elevating Histone 3 lysine trimethylation (H3K4me3), H3K9Ac and H3K14Ac
SMYD3 positive expression in HCC was significantly associated with HBV infection, microvascular invasion, poor tumor differentiation, and high TNM stage (Additional file 1: Table S1)
Summary
Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. High morbidity of metastasis is the major reason for poor prognosis of HCC patients, even of those with curative surgical treatment [2]. Accumulated evidence suggests that SMYD3 is considered to play a fundamental role in human tumorigenesis [8, 10,11,12]. These information suggest that SMYD3 may act as an epigenetic regulator in promoting HCC development and progression. The detailed molecular mechanism of how SMYD3 promotes HCC metastasis needs further investigation
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