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 in silico 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.
Highlights
MATERIALS AND METHODSLiver cancer is one of the most leading causes of cancer-associated mortality all over the world (Bray et al, 2018)
In addition to sorafenib resistance, vascular invasion and tumor metastasis are critical factors that lead to poor prognosis and malignant progression of Hepatocellular carcinoma (HCC) (Lou et al, 2018a)
The result demonstrated that expression of HDAC2, HDAC8, HDAC5, and Histone deacetylase 11 (HDAC11) was markedly increased in HCC
Summary
MATERIALS AND METHODSLiver cancer is one of the most leading causes of cancer-associated mortality all over the world (Bray et al, 2018). Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, accounting for approximately 80% of all cases (McGlynn et al, 2015). The outcome of patients with advanced HCC is still dismal because of limited therapeutic approaches (Lou et al, 2018c). Acquisition of secondary drug resistance is currently a primary limitation of sorafenib-based chemotherapy (Ding et al, 2018). In addition to sorafenib resistance, vascular invasion and tumor metastasis are critical factors that lead to poor prognosis and malignant progression of HCC (Lou et al, 2018a). It is extremely imperative to explore the detailed mechanisms responsible for sorafenib resistance, vascular invasion, and tumor metastasis and identify some promising biomarkers for prediction of HCC patients’ prognosis
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