The Transcription Factor GLI1 Mediates TGFβ1 Driven EMT in Hepatocellular Carcinoma via a SNAI1-Dependent Mechanism

Zheng, Xin; Vittar, Natalia Belén Rumie; Gai, Xiaowu; Fernández‐Barrena, Maite G.; Moser, Catherine D.; Hu, Chunling; Almada, Luciana L.; McCleary‐Wheeler, Angela L.; Elsawa, Sherine F.; Vrabel, Anne M.; Shire, Abdirashid M.; Comba, Andrea; Thorgeirsson, Snorri S.; Kim, Youngsoo; Liu, Qingguang; Fernández-Zapico, Martín E.; Roberts, Lewis R.

doi:10.1371/journal.pone.0049581

Cited by 69 publications

(62 citation statements)

References 38 publications

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“…The caspase 3/7 activity assay was conducted using an Apo-ONE® Homogeneous Caspase-3/7 Assay (Promega, Madison, WI, USA), as described in our previous study [28]. …”

Section: Methodsmentioning

confidence: 99%

Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma

et al. 2014

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BackgroundThe E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear.MethodThe Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo.ResultsIn this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo.ConclusionThese results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.

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“…The caspase 3/7 activity assay was conducted using an Apo-ONE® Homogeneous Caspase-3/7 Assay (Promega, Madison, WI, USA), as described in our previous study [28]. …”

Section: Methodsmentioning

confidence: 99%

Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma

et al. 2014

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“…cDNA synthesis and qRT-PCR analysis were done as described. 37 The ABI TaqMan probes (Applied Biosystems, Carlsbad, CA, USA) targeting PCAF (Hs00187332_m1) and 18 s rRNA (Hs99999901_s1) were used here. The relative expression of PCAF was shown as fold difference relative to 18 s rRNA.…”

Section: Methodsmentioning

confidence: 99%

P300/CBP-associated factor (PCAF) inhibits the growth of hepatocellular carcinoma by promoting cell autophagy

Jia

Dou

et al. 2016

Cell Death Dis

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Aberrant autophagic processes have been found to have fundamental roles in the pathogenesis of different kinds of tumors, including hepatocellular carcinoma (HCC). P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), performs its function by acetylating both histone and non-histone proteins. Our previous studies showed that PCAF was downregulated in HCC tissues and its high expression was significantly associated with patient survival after surgery, serving as a prognostic marker. In this study we found that overexpression of PCAF induced autophagy of HCC cells and its knockdown depressed autophagy. As type II programmed cell death, autophagy induced by PCAF-elicited cell death in HCC cells. In vivo experiments confirmed that PCAF-induced autophagy inhibited tumor growth. Subsequent in vitro experiments showed that PCAF promoted autophagy by inhibiting Akt/mTOR signaling pathway. Our findings show that PCAF is a novel modulator of autophagy in HCC, and can serve as an attractive therapeutic strategy of HCC treatment.

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“…The protocol for western immunoblotting has been described in our previous paper [12]. Briefly, cell lysates were prepared in RIPA buffer with inhibitors of proteases and with sodium orthovanadate as an inhibitor of phosphotases.…”

Section: Methodsmentioning

confidence: 99%

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

Yao

Dou

et al. 2015

Cell Physiol Biochem

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Background & Aims: To investigate the expression and prognostic value of MACC1 in patients with HCC and identify the mechanism by which MACC1 inhibits HCC cell apoptosis. Methods: MACC1 and p-AKT expression was studied using immunohistochemistry of both HCC tissues and adjacent liver tissues. qRT-PCR and western immunoblotting were used to examine the expression of target genes at the mRNA and protein levels, respectively. The MTT assay was used to assess cell viability, and cell apoptosis was determined by DAPI staining, Annexin V/PI staining and Caspase 3/7 assay. Nude mice were used to perform in vivo experiments. Results: The overexpression of MACC1 was found in HCC tissues and was correlated with poor postsurgical prognosis. There was a positive relationship between MACC1 and p-AKT expression in HCC tissues. In vitro experiments showed that MACC1 repressed HCC cell apoptosis and promoted cell growth. Knockdown of c-MET abolished the anti-apoptotic function of MACC1. Next, MACC1 was verified to activate PI3K/AKT signaling by sensitizing HGF/c-MET signaling in HCC. MACC1 overexpression enhanced the HGF-driven phosphorylation of BAD, Caspase 9 and FKHRL1 and inhibited their pro-apoptotic functions in HCC cells. Finally, MACC1 was shown to inhibit cell apoptosis and promote HCC growth in vivo. Conclusions: This investigation revealed that MACC1 overexpression predicted worse prognosis after liver resection, which was attributed to the repression of HCC cell apoptosis via a molecular mechanism in which MACC1 accelerated the activation of the HGF/c-MET/PI3K/AKT pathway and phosphorylated BAD, Caspase 9 and FKHRL1, ultimately preventing their nuclear translocation and their pro-apoptotic function.

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The Transcription Factor GLI1 Mediates TGFβ1 Driven EMT in Hepatocellular Carcinoma via a SNAI1-Dependent Mechanism

Cited by 69 publications

References 38 publications

Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma

Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma

P300/CBP-associated factor (PCAF) inhibits the growth of hepatocellular carcinoma by promoting cell autophagy

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

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