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启动子低甲基化和miR-145-5p下调介导的HDAC11过表达促进肝癌细胞对索拉非尼的耐药性和转移。

Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells.

作者信息

Wang Wenlong, Ding Bisha, Lou Weiyang, Lin Shengyou

机构信息

Intensive Care Unit, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China.

Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, College of Medicine, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang University, Hangzhou, China.

出版信息

Front Cell Dev Biol. 2020 Aug 12;8:724. doi: 10.3389/fcell.2020.00724. eCollection 2020.

DOI:10.3389/fcell.2020.00724
PMID:32903337
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7434871/
Abstract

Sorafenib resistance and tumor metastasis account for poor outcome of hepatocellular carcinoma (HCC). Histone deacetylase 11 (HDAC11) has been reported to exert oncogenic effects in several types of human cancer, but its specific functions and detailed mechanisms in HCC are not fully elucidated. Here we identified HDAC11 as a potential oncogene and promising biomarker in HCC by analysis. Histone deacetylase 11 was upregulated in sorafenib-resistant SMMC7721 compared with its parental cell. Knockdown of HDAC11 suppressed proliferation and sorafenib resistance, which may be due to inhibition of drug metabolism cytochrome P450 predicted by gene-set enrichment analysis. Histone deacetylase expression was higher in highly metastatic MHCC97H than lowly metastatic MHCC97L. Downregulation of HDAC11 significantly attenuated the migrated and invaded abilities of HCC cells. Histone deacetylase 11 was directly targeted and suppressed by miR-145-5p. Inhibition of miR-145-5p enhanced sorafenib resistance and metastasis of HCC, and these effects could be attenuated by knockdown of HDAC11. The promoter methylation level of HDAC11 was markedly decreased in HCC tissues compared with normal controls. Administration of 5'-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, facilitated HDAC11 expression in HCC cells. Our data indicate a role of miR-145-5p/HDAC11 axis in regulation of sorafenib resistance and metastasis in HCC.

摘要

索拉非尼耐药和肿瘤转移导致肝细胞癌（HCC）预后不良。据报道，组蛋白去乙酰化酶11（HDAC11）在几种人类癌症中发挥致癌作用，但其在HCC中的具体功能和详细机制尚未完全阐明。在此，我们通过分析确定HDAC11是HCC中的一种潜在癌基因和有前景的生物标志物。与亲本细胞相比，索拉非尼耐药的SMMC7721中组蛋白去乙酰化酶11上调。敲低HDAC11可抑制增殖和索拉非尼耐药，这可能是由于基因集富集分析预测的药物代谢细胞色素P450受到抑制。高转移性的MHCC97H中组蛋白去乙酰化酶表达高于低转移性的MHCC97L。HDAC11的下调显著减弱了HCC细胞的迁移和侵袭能力。组蛋白去乙酰化酶11是miR-145-5p的直接靶点并受到其抑制。抑制miR-145-5p可增强HCC的索拉非尼耐药和转移，而这些作用可通过敲低HDAC11来减弱。与正常对照相比，HCC组织中HDAC11的启动子甲基化水平明显降低。给予DNA甲基转移酶抑制剂5'-氮杂-2'-脱氧胞苷可促进HCC细胞中HDAC11的表达。我们的数据表明miR-145-5p/HDAC11轴在调节HCC的索拉非尼耐药和转移中起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/8a6839ace428/fcell-08-00724-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/62cb84e57fcc/fcell-08-00724-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/994ffb917316/fcell-08-00724-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/3bc3af3a1c92/fcell-08-00724-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/c6ed3ca14b0c/fcell-08-00724-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/8a6839ace428/fcell-08-00724-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/62cb84e57fcc/fcell-08-00724-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/4f41d642992c/fcell-08-00724-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/994ffb917316/fcell-08-00724-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/cdfafb60f6df/fcell-08-00724-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/3bc3af3a1c92/fcell-08-00724-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/9e1d21daf3ca/fcell-08-00724-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/c6ed3ca14b0c/fcell-08-00724-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/36ed/7434871/8a6839ace428/fcell-08-00724-g008.jpg

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