Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and Downregulation of FLIP

Upregulation of histone acetylation plays a critical role in the dysregulation of transcription. It alters the structure of chromatin, which leads to the onset of cancer. Histone deacetylase inhibitors may therefore be a promising way to limit cancer progression. In this study, we examined the effects of droxinostat on the growth of HT-29 colon cancer cells. Our results show that droxinostat effectively inhibited cell growth and colony-forming ability by inducing cellular apoptosis and ROS production in HT-29 cells. Notably, the apoptotic inhibitor Z-VAD-FMK significantly decreased the levels of cellular apoptosis and the antioxidant γ-tocotrienol (GT3) significantly decreased ROS production induced by droxinostat treatment. Z-VAD-FMK and GT3 also partially reversed the negative growth effects of droxinstat on HT-29 cells. GT3 treatment decreased cellular apoptosis and increased colony-forming ability upon droxinostat administration. Z-VAD-FMK treatment also partially decreased droxinostat-induced ROS production. Our findings suggest that the effects of droxinostat on colon cancer cells are mediated by the induction of oxidative stress and apoptotic cell death.Electronic supplementary materialThe online version of this article (10.1186/s11658-018-0101-5) contains supplementary material, which is available to authorized users.

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“…5d ). A previous study showed that droxinostat decreased the expression of c-FLIP [ 28 , 29 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of c-FLIP was decreased by droxinostat treatment in HT-29 cells, which resulted in the activation of the extrinsic apoptotic pathway. Waugh et al and Zhang et al also found that HDACIs, such as droxinostat and SAHA, downregulated c-FLIP expression in prostatic cancer cells and hepatocellular carcinoma cells [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Droxinostat sensitizes human colon cancer cells to apoptotic cell death via induction of oxidative stress

et al. 2018

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“…8 Droxinostat, a type of histone deacetylase inhibitor, suppresses HDAC3 expression and induces histone acetylation and HCC cell death through activation of the mitochondrial apoptotic pathway and downregulation of FLIP, supporting its potential application in the treatment of HCC. 7 A recent study reported that HDAC3 participates in hepatitis C virus (HCV) replication, and RGFP966 may be a potential treatment for diseases associated with HCV infection such as HCC, although no change in cell viability following treatment of 10μM RGFP966 in HCV-infected Huh7 cells. 20 In accordance with this report, we found that RGFP966 mildly inhibits cell proliferation of Huh7 and HepG2 cells at a higher concentration, whereas remarkable inhibitory effect was shown in PLC/PRF/ 5 cells following treatment of 10μM RGFP966 (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Histone deacetylases (HDACs) play major roles in diverse biological functions, and HDAC inhibitors show clinical promise for the treatment of cancers, including HCC. [6][7][8] Based on sequence similarity, HDAC family are divided into four subfamilies: classes I, IIa, IIb, III, and IV. HDAC3 was the third one to be identified of HDACs and belongs to class I HDACs.…”

Section: Introductionmentioning

confidence: 99%

<p>RGFP966 Suppresses Tumor Growth and Migration Through Inhibition of EGFR Expression in Hepatocellular Carcinoma Cells in vitro</p>

Yang

Jiang

et al. 2020

DDDT

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Purpose: Histone deacetylase 3 (HDAC3) has been suggested to play a role in hepatocellular carcinoma (HCC). In the present report, we aimed to identify the effects of RGFP966, a specific HDAC3 inhibitor, on the cell proliferation and migration of HCC cell lines. Methods: Human HCC cell lines, which were identified using short tandem repeat (STR) DNA profiling analysis, were used in this report. Cell proliferation assay was used to identify the growth viability of cells. Wound healing and transwell assay were used to identify the migration ability of cells. Further, a human phospho-receptor tyrosine kinases array kit was used to screen out RGFP966 effects on key receptor tyrosine kinases. Then, the mRNA expression was quantified by real-time PCR, and protein expression was identified by Western blot immunoassay. Results: We found that RGFP966 inhibited both proliferation and migration of HCC cells. Further, RGFP966 represses the expression and phosphorylation levels of epidermal growth factor receptor (EGFR) in HCC cells. Moreover, HDAC3 is involved in the inhibition of EGFR by RGFP966. Overall, we elucidated an inhibitive function of RGFP966 in HCC progression. Conclusion: RGFP966 inhibits EGFR signaling pathway and suppresses proliferation and migration of HCC cells.

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“…Droxinostat, a HDAC inhibitor, was found to suppress HDAC3 expression and induce acetylation of histones H3 and H4. This compound can inhibit cell proliferation and induce apoptosis in HCC cell lines by activating mitochondrial apoptotic pathways (31). A novel histone deacetylase inhibitor, MPT0G009 was reported to be a potential new candidate drug for HCC therapy.…”

Section: Applications Of Hdac Inhibitor For the Therapy Of Hccmentioning

confidence: 99%

Cytokeratin 18-associated Histone 3 Modulation in Hepatocellular Carcinoma: A Mini Review

Lai

Cheng

Lai

et al. 2017

CGP

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Abstract.Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality in Taiwan. HCC cells exhibit different morphological features in divergent shapes and having pleomorphic nuclei from normal liver cells. Microtubules (MTs), intermediate filaments (IFs), and microfilaments (MFs) are major components of the cytoskeleton that are essential to maintain the integrity of eukaryotic cells (1). Proper cross-linking structures among these cytoskeletal proteins are crucial for intracellular architectures and normal cellular morphology. Plectin exhibits the binding sites accessible to IFs, MTs and MFs rendering the interaction with a variety of cytoskeletal components to maintain the integrity of the cytoskeletal network (2). The rope-like IFs have a mean diameter of 10 nm and mainly play a role in maintaining the shape and mechanical integrity of a cell (3). In human hepatocytes, a cytokeratin (CK) pair composed of CK8 (type II, 52 kD) and CK18 (type I, 45 kD) renders IFs (4). CKs are required for maintaining the integrity of hepatocytes (5). Altered expression of keratin genes were associated with chronic hepatitis, increased hepatocyte fragility and decreased bile secretion (6).In eukaryotic nucleus, the organization and packaging of DNA are achieved by addition of histone proteins to form chromatin. Post-translational modifications of histones, such as acetylation, phosphorylation, methylation and ADPribosylation, frequently alter the structure of chromatin (7). Epigenetic modifications of histone, especially acetylation status, altering the chromatin structure are involved in gene expression and further intervened in the pathogenesis of cancer. Two types of enzymes, including histone acetyltransferases (HATs) and histone deacetylases (HDACs), affect the acetylation status of histones. Recently it was reported that alterations in the activities of HDACs, as well as aberrant acetylation of histone, lead to diseases including cancer (8). HDACs catalyze histone deacetylation and repress transcription of specific genes, such as p21, resulting in cell-cycle activation and cell proliferation (9).The investigation of histones in our laboratory originated in a study of CK18, in which we found that CK18 was coimmunoprecipitated with histone H3 in human HCC, but not in normal liver. We speculated that both histone H3 and CK18 were modulated in HCC, which was shown in the co-219

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Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and Downregulation of FLIP

Cited by 17 publications

References 28 publications

Droxinostat sensitizes human colon cancer cells to apoptotic cell death via induction of oxidative stress

Droxinostat sensitizes human colon cancer cells to apoptotic cell death via induction of oxidative stress

<p>RGFP966 Suppresses Tumor Growth and Migration Through Inhibition of EGFR Expression in Hepatocellular Carcinoma Cells in vitro</p>

Cytokeratin 18-associated Histone 3 Modulation in Hepatocellular Carcinoma: A Mini Review

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