Histone deacetylase inhibitors for treatment of hepatocellular carcinoma

Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity of HCC, rendering it more susceptible to oxidative stress and cell death. Change in the transcriptome of HCC was analyzed by RNA-seq and validated using real-time quantitative polymerase chain reaction (qPCR) and Western blot. Cell death of HCC was analyzed by fluorescence-activated cell sorting (FACS). Protein localization and binding on the target gene promoters were investigated by immunofluorescence (IF) and chromatin immunoprecipitation (ChIP), respectively. Glutathione peroxidase 8 (GPX8) was highly down-regulated in HCC upon oxidative stress and HDACi co-treatment. Oxidative stress and HDACi enhanced the expression and transcriptional activities of ER-stress-related genes. N-acetyl-cysteine (NAC) supplementation reversed the oxidative stress and HDACi-induced apoptosis in HCC. HDACi significantly enhanced the effect of ER stressors on HCC cell death. GPX8 overexpression reversed the activation of ER stress signaling and apoptosis induced by oxidative stress and HDACi. In conclusion, HDACi suppresses the expression of GPX8, which sensitizes HCC to ER stress and apoptosis by oxidative stress.

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Faculty Opinions recommendation of Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11536956.12583054 ◽

2011 ◽

Author(s):

Fabio Marra ◽

Giovanni Di Maira ◽

Elisa Vivoli

Keyword(s):

Hepatocellular Carcinoma ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Carcinoma Cells ◽

Topoisomerase Iiα ◽

Hepatocellular Carcinoma Cells

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Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective

Surgical Oncology ◽

10.1016/j.suronc.2018.07.015 ◽

2018 ◽

Vol 27 (4) ◽

pp. 611-618 ◽

Cited By ~ 26

Author(s):

Diamantis I. Tsilimigras ◽

Ioannis Ntanasis-Stathopoulos ◽

Demetrios Moris ◽

Eleftherios Spartalis ◽

Timothy M. Pawlik

Keyword(s):

Hepatocellular Carcinoma ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Therapeutic Perspective

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Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro

Cancers ◽

10.3390/cancers11101587 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1587 ◽

Cited By ~ 9

Author(s):

Kim Freese ◽

Tatjana Seitz ◽

Peter Dietrich ◽

Serene M.L. Lee ◽

Wolfgang E. Thasler ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Molecular Mechanisms ◽

Trichostatin A ◽

Class I ◽

Common Mechanism ◽

Promising Therapeutic Approach ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is a leading cause for deaths worldwide. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy. However, most pharmacological HDACi unselectively block different HDAC classes and their molecular mechanisms of action are only incompletely understood. The aim of this study was to systematically analyze expressions of different HDAC classes in HCC cells and tissues and to functionally analyze the effect of the HDACi suberanilohydroxamic acid (SAHA) and trichostatin A (TSA) on the tumorigenicity of HCC cells. The gene expression of all HDAC classes was significantly increased in human HCC cell lines (Hep3B, HepG2, PLC, HuH7) compared to primary human hepatocytes (PHH). The analysis of HCC patient data showed the increased expression of several HDACs in HCC tissues compared to non-tumorous liver. However, there was no unified picture of regulation in three different HCC patient datasets and we observed a strong variation in the gene expression of different HDACs in tumorous as well as non-tumorous liver. Still, there was a strong correlation in the expression of HDAC class IIa (HDAC4, 5, 7, 9) as well as HDAC2 and 8 (class I) and HDAC10 (class IIb) and HDAC11 (class IV) in HCC tissues of individual patients. This might indicate a common mechanism of the regulation of these HDACs in HCC. The Cancer Genome Atlas (TCGA) dataset analysis revealed that HDAC4, HDAC7 and HDAC9 as well as HDAC class I members HDAC1 and HDAC2 is significantly correlated with patient survival. Furthermore, we observed that SAHA and TSA reduced the proliferation, clonogenicity and migratory potential of HCC cells. SAHA but not TSA induced features of senescence in HCC cells. Additionally, HDACi enhanced the efficacy of sorafenib in killing sorafenib-susceptible cells. Moreover, HDACi reestablished sorafenib sensitivity in resistant HCC cells. In summary, HDACs are significantly but differently increased in HCC, which may be exploited to develop more targeted therapeutic approaches. HDACi affect different facets of the tumorigenicity of HCC cells and appears to be a promising therapeutic approach alone or in combination with sorafenib.

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