The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma

Wu, Jian; Du, Chengli; Lv, Zhen; Ding, Chaofeng; Cheng, Jun; Xie, Haiyang; Zhou, Lin; Zheng, Shusen

doi:10.1007/s10620-013-2867-7

Cited by 80 publications

(77 citation statements)

References 28 publications

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“…Overexpression of HDAC8 has been reported in a considerable number of different cancer entities [26,34,36,37]. In neuroblastoma, in particular, HDAC8 expression was significantly correlated with further poor prognostic Figure 11 Compensation mechanism after HDAC8 knockdown in RT-112, VM-CUB1, SW-1710, 639-V and UM-UC-3 cells.…”

Section: Discussionmentioning

confidence: 97%

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Lehmann

Hoffmann

Koch

et al. 2014

J Exp Clin Cancer Res

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Background: Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. Methods: We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. Results: Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC 50 9 -21 μM). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line-and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. Conclusions: Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer.

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Section: Discussionmentioning

confidence: 97%

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Lehmann

Hoffmann

Koch

et al. 2014

J Exp Clin Cancer Res

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“…HDAC8 expression is restricted to specific cell type showing smooth muscle differentiation in normal human tissues (34,36). Although HDAC8 has been shown to promote growth of a number of cancer types (25), (37)(38)(39) and contribute to poor prognosis in childhood neuroblastoma (40), the molecular actions of HDAC8 in cancer remained poorly defined. Although specific HDACs can deacetylate nonhistone proteins (35), emerging data suggest that direct gene repression by HDAC8 might control key pathologic processes (41,42).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma

et al. 2015

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The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesitypromoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLDassociated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G 2 -M phase cell-cycle arrest and stimulated b-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active b-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients. Cancer Res; 75(22); 4803-16. Ó2015 AACR.

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“…The level is similar in cancer and corresponding healthy tissues, with a tendency towards higher expression in cancer tissues [31,43]. Knockdown of HDAC8 by RNA interference (RNAi) inhibits proliferation of human lung, colon, and cervical cancer cell lines (Figure 2), and the upregulation of HDAC8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma [31,45].…”

Section: Hdac8 and Diseasesmentioning

confidence: 96%

“…A quest for further substrates identified multiple partners, including structural maintenance of chromosomes 3 (SMC3), p53, ERRa, and inv(16) fusion protein [13,14,31,32] (Figure 1; see Glossary). The latest additions are retinoic acid induced 1 (RAI1), zinc finger, RAN-binding domain containing 2 (ZRANB2), nuclear receptor co-activator 3 (NCOA3), thyroid hormone receptor-associated protein 3 (THRAP3), AT-rich interactive domain-containing protein 1A (ARID1A), and cortactin [9,15].…”

Section: Hdac8 Substratesmentioning

confidence: 99%

HDAC8: a multifaceted target for therapeutic interventions

Chakrabarti

Oehme

Witt

et al. 2015

Trends in Pharmacological Sciences

209

157

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Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.

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The Up-Regulation of Histone Deacetylase 8 Promotes Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma

Abstract: Our study revealed that HDAC8 was overexpressed in HCC. HDAC8 knockdown suppresses tumor growth and enhances apoptosis in HCC via elevating the expression of p53 and acetylation of p53 at Lys382. HDAC8 might serve as a potential therapeutic target in HCC.

Cited by 80 publications

References 28 publications

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma

HDAC8: a multifaceted target for therapeutic interventions

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