PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0890-4) contains supplementary material, which is available to authorized users.

The Autophagy Machinery Contributes to E-cadherin Turnover in Breast Cancer

“…The fact that E-cadherin may be downregulated through the activation of autophagy has been already demonstrated on melanoma and hepatoma cells in which SIRT1 and SPHK1, respectively, regulate this process (Liu et al, 2017;Sun et al, 2018;Zhou et al, 2018). Here we went further by demonstrating that in breast cancer E-cadherin is delivered to autophagosomes.…”

“…In other tumors, the CDH1 gene is transcriptionally repressed ( Nieto et al, 2016 ; Kourtidis et al, 2017 ). Augmented endocytosis of E-cadherin has also been reported ( Jones et al, 2006 ; Kourtidis et al, 2017 ) and autophagy-induced degradation, due to overexpression of SIRT1, SPHK1, or PHF8 have been described in melanoma and hepatocarcinoma ( Liu et al, 2017 ; Sun et al, 2018 ; Zhou et al, 2018 ). Yet, the mechanisms whereby autophagy impacts on E-cadherin expression in the setting of BC are not fully elucidated.…”

LRG1 Suppresses Migration and Invasion of Esophageal Squamous Cell Carcinoma by Modulating Epithelial to Mesenchymal Transition

“…EMT is the biological process by which epithelial cells are transformed into mesenchymal phenotype cells and acquire the ability to migrate and invade [21,22]. This process can downregulate E-cadherin but upregulate N-cadherin, vimentin (VIM) and slug through modulating EMT-related signaling pathways [23,24]. We therefore examined whether enhanced migration and invasion of ESCC cells with LRG1 knockdown was achieved by promoting EMT.…”

Synergistic interplay between PHF8 and HER2 signaling contributes to breast cancer development and drug resistance

“…Oncogenic functions of PHF8 have been recognized in various types of cancer (Bjorkman et al, 2012;Maina et al, 2016;Shen et al, 2014;Sun et al, 2013;Zhou et al, 2018). We ) and Wang Q et al (Wang et al, 2016) discovered such functions of PHF8 in breast cancers and reported the significant increase of PHF8 mRNA levels in several subtypes of breast cancers.…”

“…These studies also revealed a general transcriptional coactivator function of PHF8. The following studies demonstrated the overexpression and oncogenic functions of PHF8 in various types of cancers such as prostate cancer (Bjorkman et al, 2012;Maina et al, 2016), esophageal squamous cell carcinoma (Sun et al, 2013), lung cancer (Shen et al, 2014), and hepatocellular carcinoma (Zhou et al, 2018). Beyond overexpression, the post-transcriptional and posttranslational regulations of PHF8 were also recently elucidated.…”