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YY1 promotes HDAC1 expression and decreases sensitivity of hepatocellular carcinoma cells to HDAC inhibitor.

ABSTRACT: YY1 is a DNA-binding transcription factor and reported to be involved in cancer progression. Histone deacetylase inhibitor (HDACi) could inhibit proliferation and promote apoptosis of Hepatocellular carcinoma (HCC) cells. However, it is unclear about the roles of YY1 in the sensitivity of HCC cells to HDACi. In this study, firstly, we identified two drug-response profiles to HDACi in HCC cell lines, while our results showed that HDAC1 expression was positively correlated with YY1 in HCC cell lines and primary tumor tissues. Secondly, YY1 decreased the sensitivity of HCC cells to HDACi in vitro and in vivo. Furthermore, we found that YY1 promoted HDAC1 expression by binding to its promoter, while HDAC1 in turn up-regulated the expression of YY1. In conclusion, our results showed that YY1 could reduce the sensitivity of HCC cells to HDACi and might be a potential therapeutic target in HCC.

SUBMITTER: Dong S

PROVIDER: S-EPMC5522268 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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YY1 promotes HDAC1 expression and decreases sensitivity of hepatocellular carcinoma cells to HDAC inhibitor.

Dong Sheng S Ma Xiang X Wang Zusen Z Han Bing B Zou Hao H Wu Zehua Z Zang Yunjin Y Zhuang Likun L

Oncotarget 20170601 25

YY1 is a DNA-binding transcription factor and reported to be involved in cancer progression. Histone deacetylase inhibitor (HDACi) could inhibit proliferation and promote apoptosis of Hepatocellular carcinoma (HCC) cells. However, it is unclear about the roles of YY1 in the sensitivity of HCC cells to HDACi. In this study, firstly, we identified two drug-response profiles to HDACi in HCC cell lines, while our results showed that HDAC1 expression was positively correlated with YY1 in HCC cell lin ...[more]

PMID: 28489564

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Project description:BackgroundAdaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified.MethodsBy data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1.ResultsWe found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice.ConclusionsOur findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

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YY1 promotes HDAC1 expression and decreases sensitivity of hepatocellular carcinoma cells to HDAC inhibitor.

Publications

YY1 promotes HDAC1 expression and decreases sensitivity of hepatocellular carcinoma cells to HDAC inhibitor.

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