Overexpression of HDAC6 suppresses tumor cell proliferation and metastasis by inhibition of the canonical Wnt/β‑catenin signaling pathway in hepatocellular carcinoma

Yin, Zhusheng; Xu, Wei; Xu, Hao; Zheng, Junnian; Gu, Yuming

doi:10.3892/ol.2018.9504

Cited by 16 publications

(14 citation statements)

References 40 publications

(53 reference statements)

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“…Interestingly, we show that HDAC6, a deacetylase primarily localized in the cytoplasm, negatively regulates the acetylation and phosphorylation of β-catenin, i.e. positively regulates Wnt/β-catenin signaling, in agreement with previous reports (Li et al, 2008; Wang et al, 2014a) but in contrary to another study in hepatocellular carcinoma cells (Yin et al, 2018); and we find that HDAC6 is critical for the β-catenin signaling pathway to promote FMOD expression, and reveal HDAC6 as a component and regulator of the canonical Wnt/β-catenin pathway right upstream of β-catenin, and also as a direct target of Aspirin inhibition of this pathway and breast cancer (see below).…”

Section: Discussionsupporting

confidence: 92%

Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin

et al. 2019

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Emerging evidence suggests that fibromodulin (FMOD), an extracellular matrix protein, is associated with cancer, and yet little is known about the regulation of FMOD expression and its role in cancer metastasis. Aspirin, a classic anti-inflammatory drug, has been indicated to offer anticancer benefits, but its action targets and mechanisms remain obscure. In the present study using cell lines, animal model and database analysis, we show that FMOD is crucial for breast cancer cell migration and invasion (BCCMI) via activation of ERK; expression of FMOD is regulated positively by the Wnt/β-catenin pathway, wherein the β-catenin/TCF4/LEF1 complex binds the FMOD promoter to transcribe FMOD. Aspirin inhibits BCCMI by attenuating Wnt/β-catenin signaling and suppressing FMOD expression via inhibiting deacetylation of β-catenin by histone deacetylase 6 (HDAC6) leading to β-catenin phosphorylation and cytoplasmic degradation. Moreover, expression of the transcriptional complex components β-catenin/TCF4/LEF1 is upregulated by the Wnt/β-catenin pathway, constituting positive feedback loops that amplify its signal output. Our findings identify a critical role of FMOD in cancer metastasis, reveal a mechanism regulating FMOD transcription and impacting tumor metastasis, uncover action targets and mechanism for the anticancer activity of Aspirin, and expand the understanding of the Wnt/β-catenin pathway and tumor metastasis, which are valuable for development of cancer therapeutics.

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Section: Discussionsupporting

confidence: 92%

Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin

et al. 2019

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“…And the regulation of WNT signaling was also researched in HCC. It was reported that HDAC6 inhibits WNT pathway to suppress cell proliferation in HCC [50]. Herein, we unmasked that lncRNA OIP5-AS1 targeted to miR-300 and enhanced HCC cell growth.…”

Section: Discussionmentioning

confidence: 94%

OIP5-AS1 contributes to tumorigenesis in hepatocellular carcinoma by miR-300/YY1-activated WNT pathway

et al. 2020

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Background It has reported that long non-coding RNAs (lncRNAs) exerted regulatory functions by targeting specific genes through a competing endogenous RNA (ceRNA) pathway. LncRNA OIP5-AS1 has been identified as a tumor-enhancer in several tumor types. Nonetheless, its molecular mechanism in HCC remains to be masked. Aim of the study This study was aimed at exploring whether and how OIP5-AS1 exert functions in HCC. Methods qRT-PCR and western blot were employed for detecting gene expression. CCK-8, colony formation and EdU assays were implemented to evaluate the proliferative ability of HCC cells. Caspase-3 activity and flow cytometry analyses were implemented to determine cell apoptosis and cell cycle distribution. RNA pull down, ChIP, RIP and luciferase reporter assays explored the interplays between molecules. Results YY1 was upregulated in HCC cells, and silenced YY1 restrained HCC cell proliferation in vitro and hampered tumor growth in vivo. Later, we discovered that miR-300 could regulate WNT pathway via targeting YY1. Furthermore, OIP5-AS1 was identified as the sponge of miR-300 and promoted cell growth in HCC. Importantly, YY1 transcriptionally activate OIP5-AS1 in turn. Rescue experiments indicated that miR-300 inhibition or YY1 overexpression abrogated the inhibitive effect of OIP5-AS1 silencing on the malignant growth of HCC cells. Conclusions OIP5-AS1/miR-300/YY1 feedback loop facilitates cell growth in HCC by activating WNT pathway.

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“…For example, a recent study (31) has described that deletion of HDAC6 in T helper 17 (Th17) cells impedes HCC growth by enhancing the production of antitumor cytokines and CD8 T cell mediated antitumor response in mice. However, other studies have shown that HDAC6 is a tumor suppressor for HCC (32)(33)(34). It is reported that low expression of HDAC6 in liver cancer specimens is highly associated with poor prognosis of HCC patients (32).…”

Section: Discussionmentioning

confidence: 99%

Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcoholic liver disease

Yang

Sungwung

Jung

et al. 2020

Preprint

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Background: It is unknown whether liver sinusoidal endothelial cells (LSECs) metabolize alcohol. Chronic alcohol consumption decreases endothelial nitric oxide synthase (eNOS)-derived NO production typical of LSEC dysfunction. Heat shock protein 90 (Hsp90) interacts with eNOS to increase its activity. Cytochrome P450 2E1 (CYP2E1) is a key enzyme in alcohol metabolism and facilitates protein acetylation via acetyl-CoA, but its expression in LSECs is unknown. This study investigates alcohol metabolism by LSECs, the mechanism of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury. Methods: Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs using an adeno-associated virus (AAV)-mediated gene delivery system to decrease Hsp90 acetylation in ethanol fed mice. Results: LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with eNOS along with a decrease in NO production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyper-acetylation mutant decreased NO production, compared with wildtype Hsp90. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. Adeno-associated virus 8 (AAV8)-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90s interaction with eNOS and ameliorated alcohol-induced liver injury in mice. Conclusion: Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy.

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Overexpression of HDAC6 suppresses tumor cell proliferation and metastasis by inhibition of the canonical Wnt/β‑catenin signaling pathway in hepatocellular carcinoma

Cited by 16 publications

References 40 publications

Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin

Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin

OIP5-AS1 contributes to tumorigenesis in hepatocellular carcinoma by miR-300/YY1-activated WNT pathway

Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcoholic liver disease

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