PCAF inhibits hepatocellular carcinoma metastasis by inhibition of epithelial-mesenchymal transition by targeting Gli-1

Li, Qing; Liu, Zhikui; Xu, Meng; Xue, Yumo; Yao, Bowen; Dou, Changwei; Jia, Yuli; Wang, Yufeng; Tu, Kangsheng; Zheng, Xin; Yao, Yingmin

doi:10.1016/j.canlet.2016.02.053

Cited by 36 publications

(30 citation statements)

References 35 publications

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“…Accumulating reports have shown that the Hh pathway has a vital character in different tumors, including HCC [27-29]. Our previous studies reveal that the overexpressed of GLI1 in HCC are associated with the invasiveness of HCC, and its up-regulation predicts poor prognosis and represent the progressive stages of HCC [30]. GLI1 is a key transcription factor of Hh signaling.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu¹,

Tu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. Methods: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. Results: In present study, we first observed a strongly positive correlation between HIF-1α and GLI1 expression in HCC tissues. Then, we showed that hypoxia significantly promoted EMT process and invasion of HCC cells, associated with activating the non-canonical Hh pathway without affecting SHH and PTCH1 expression. HIF-1α knockdown mitigated hypoxia-induced SMO and GLI1 expression, EMT invasion of HCC cells. Moreover, the SMO inhibitor or GLI1 siRNA also reversed the hypoxia-driven EMT and invasion of HCC cells under hypoxia condition. Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in HCC cells. In addition, we found that hypoxia increased ROS production and that ROS inhibitors (NAC) blocked GLI1-dependent EMT process and invasion under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is involved in hypoxia-induced ROS production. NOX4 expression was found to be increased at both mRNA and protein levels in hypoxic HCC cells. Furthermore, siRNA-mediated knockdown of NOX4 expression abolished hypoxia induced ROS generation and GLI1-dependent activation and invasion of HCC cells. Conclusion: Our findings indicate that hypoxia triggers ROS-mediated GLI1-dependent EMT progress and invasion of HCC cells through induction of NOX4 expression. Thus, hypoxia-driven ROS mediated non-canonical Hh signaling may play an important role in the initiation of EMT and provides a potential marker for cancer prevention and treatment.

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Section: Introductionmentioning

confidence: 99%

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu¹,

Tu²,

Wang³

et al. 2017

Cell Physiol Biochem

Self Cite

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“…The different findings in these reports and our studies is unknown but may be related to different metastatic mechanisms among different tumor types, or differences in the model systems (genetically engineered conditional knockouts versus orthotopic xenografts with targeted knockdowns). Notably, even more recent evidence has linked SNAIL-mediated EMT and metastasis across multiple tumor types: hepatocellular carcinoma (SNAIL mediated EMT) [42, 43], breast cancer [44], osteosarcoma [45], and pancreatic cancer (SNAIL-mediated EMT) [46]. …”

Section: Discussionmentioning

confidence: 99%

Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis

et al. 2016

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Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic “recycling” technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC’s) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

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“…In addition, its overexpression induces HCC cell apoptosis and autophagy . PCAF has also been proposed to act as a metastasis suppressor of HCC by restraining the activity of transcription factor glioma‐associated oncogene homologue‐1 (Gli1), thus inhibiting the epithelial‐to‐mesenchymal transition (EMT) of HCC cells . EMT is controlled by a group of transcriptional repressors, including Gli1.…”

Section: Pcaf In Liver Cancer and Tumour Growthmentioning

confidence: 99%

PCAF fine‐tunes hepatic metabolic syndrome, inflammatory disease, and cancer

Yao

Shao

Zheng

et al. 2018

J Cellular Molecular Medi

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The P300/CBP‐associating factor (PCAF), a histone acetyltransferase, is involved in metabolic and pathogenic diseases, particularly of the liver. The effects of PCAF on fine‐tuning liver diseases are extremely complex and vary according to different pathological conditions. This enzyme has dichotomous functions, depending on differently modified sites, which regulate the activities of various enzymes, metabolic functions, and gene expression. Here, we summarize the most recent findings on the functions and targets of PCAF in various metabolic and immunological processes in the liver and review these new discoveries and models of PCAF biology in three areas: hepatic metabolic syndrome, inflammatory disease, and cancer. Finally, we discuss the potential implications of these findings for therapeutic interventions in liver diseases.

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PCAF inhibits hepatocellular carcinoma metastasis by inhibition of epithelial-mesenchymal transition by targeting Gli-1

Cited by 36 publications

References 35 publications

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis

PCAF fine‐tunes hepatic metabolic syndrome, inflammatory disease, and cancer

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