Abstract
BackgroundPlant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. However, little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression.MethodsPHF8 expression pattern was investigated by informatic analysis and verified by RT-qPCR and immunochemistry in HCC tissues and cell lines. CCK8, xenograft tumor model, transwell assay, and tandem mCherry-GFP-LC3 fusion protein assay were utilized to assess the effects of PHF8 on proliferation, metastasis and autophagy of HCC cells in vitro and in vivo. ChIP, immunoblot analysis, rescue experiments and inhibitor treatment were used to clarify the mechanism by which PHF8 facilitated EMT, metastasis and autophagy.ResultsPHF8 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival and disease-relapse free survival. Furthermore, PHF8-knockdown dramatically suppressed cell growth, migration, invasion and autophagy, and the expression of SNAI1, VIM, N-cadherin and FIP200, and increased E-cadherin level, while PHF8-overexpression led to the opposite results. Additionally, FIP200 augmentation reversed the inhibited effects of PHF8-siliencing on tumor migration, invasion and autophagy. Mechanistically, PHF8 was involved in transcriptionally regulating the expression of SNAI1, VIM and FIP200, rather than N-cadherin and E-cadherin. Noticeably, E-cadherin degradation could be accelerated by PHF8-mediated FIP200-dependent autophagy, a crucial pathway complementary to transcriptional repression of E-cadherin by SNAI1 activation.ConclusionThese findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in HCC. PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC.
Highlights
Plant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors
Our results revealed that the high expression of PHF8 was associated with the more aggressive phenotypes and worse outcome, and enhanced autophagy, invasion and migration through upregulation of FIP200, SNAI1, VIM and CDH2/N-cadherin and E-cadherin attenuation, which could be accelerated by FIP200-dependent autophagy
PHF8 upregulation is quite prevalent and serves as an independent risk factor for poor prognosis and relapse in hepatocellular carcinoma (HCC) To evaluate the expression pattern of PHF8 in HCCs, we initially analyzed two microarray datasets from Gene expression omnibus (GEO) database (Fig. 1a) and revealed higher expression of PHF8 in HCCs than normal liver tissues. This finding was in line with the analysis of another two datasets from Oncomine Database (Fig. 1b), and supported by the results of remarkable upregulation of PHF8 at both mRNA and protein level in HCC cells compared with normal liver cells, and in HCC tissues in comparison with adjacent normal liver tissues (Fig. 1c-e)
Summary
Plant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. Little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression. PHF8 binds to promoter sites of approximate one third of human genes and activates their expression by erasing repressive histone markers, including H3K9me1/2, H3K27me and H4K20me1 [7,8,9, 12]. These remarkable features imply that the ectopic expression of PHF8 is potentially correlated with genetic and environmental disease such as human cancer. Little is known about the expression pattern and roles of PHF8 in HCC
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