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

Lehmann, Maria; Hoffmann, Michèle J.; Koch, A.; Ulrich, Scott M.; Schulz, Wolfgang A.; Niegisch, Günter

doi:10.1186/preaccept-5627314451282443

Cited by 6 publications

(13 citation statements)

References 35 publications

(44 reference statements)

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“…The expression of HDAC8 has been determined in several cancer tissues. Upregulation of HDAC8 was detected in colon, urothelial, ovarian and endometrial cancers (13,20,22,23), and high HDAC8 expression was associated with markers of poor prognosis and poor overall survival in neuroblastoma (16). Likewise, our results also showed that HDAC8 were markedly upregulated in both OSCC tissues and OSCC cell lines.…”

Section: Discussionsupporting

confidence: 70%

“…The most frequently studied and best-characterized human HDACs are HDAC1 and HDAC2. Also, HDAC8 is most recently identified class I HDAC and the role of HDAC8 in normal and cancer cells remains unclear (20,21). The expression of HDAC8 has been determined in several cancer tissues.…”

Section: Discussionmentioning

confidence: 99%

“…It could be demonstrated that the subcellular localization of HDAC can be nuclear as well as cytoplasmic. The class I HDACs are found primarily in the nucleus of most cell types and form nuclear multiprotein complexes that interact with other chromatin modifiers and transcription factors (10,20). Unlike other class I HDACs, the subcellular localization of HDAC8 seems to vary with cell types (20,28).…”

Section: Discussionmentioning

confidence: 99%

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Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Ahn

Yoon

2016

Oncology Reports

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The overexpression of histone deacetylases (HDACs) has been observed in many cancers and inhibition of specific HDAC has emerged as a new target for cancer therapy. The present study examined the expression of HDAC8 and the inhibitory effect of HDAC8 in oral squamous cell carcinoma (OSCC). The expression of HDAC8 was measured in human OSCC tissues and OSCC cell lines using immunohistochemistry and immunoblotting. HDAC8 was knocked down in OSCC cells by transfection with HDAC8 siRNAs and cell proliferation was quantified. Apoptosis and autophagy were measured using flow cytometry and immunoblotting. HDAC8 were overexpressed in OSCC tissues and OSCC cells, mainly localized in the cytoplasm. HDAC8 siRNAs effectively reduced the level of HDAC8 expression and HDAC8 silencing significantly inhibited the proliferation of OSCC cells. HDAC8 knockdown induced apoptotic cell death through caspases activation and pro-survival autophagy in OSCC cells. Combination with HDAC silencing and autophagy inhibition enhanced cell death by increasing apoptosis in OSCC cells. This study suggests that inhibition of HDAC8 might become a novel therapeutic strategy for OSCC.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Ahn

Yoon

2016

Oncology Reports

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“…In the following experiments, all cells were treated with 3 nmol/L romidepsin, 0.5 mmol/L givinostat, and 2.5 mmol/L SAHA (approximate IC 50 s in UCCs). Our group has characterized the impact of SAHA on UCCs previously (6,20,21). All HDAC inhibitors, most strongly romidepsin, significantly enhanced the level of acetylated histones H3 and H4 in UCCs (Fig.…”

Section: Hdac Inhibitors Selectively Targeting Hdac1 and Hdac2 Show Smentioning

confidence: 99%

“…In contrast, neither selective inhibition of HDAC8 nor HDAC6 was efficacious (20,21). We therefore sought to evaluate the efficacy of specific HDAC1 and HDAC2 inhibition in urothelial carcinoma cell lines (UCC) by either siRNA-mediated knockdown or specific pharmacologic inhibition with the class I HDAC inhibitors romidepsin (FK228; ref.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms

Pinkerneil

Hoffmann

Deenen

et al. 2016

Molecular Cancer Therapeutics

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Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line-and HDAC-dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC 50 , 3.36 nmol/L-4.59 mmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy.Mol Cancer Ther; 15(2); 299-312. Ó2016 AACR.

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Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer

Chen

Tan

Gao

et al. 2015

J Exp Clin Cancer Res

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BackgroundRibosomal protein S6 (rpS6), a component of the 40S ribosomal subunit, is involved in multiple cellular bioactivities. However, its clinicopathological significance in non-small cell lung cancer (NSCLC) is poorly understood.MethodsExpressions of total rpS6 (t-rpS6) and phosphorylated rpS6 (Ser235/236, p-rpS6) were detected immunohistochemically in 316 NSCLC tissues and 82 adjacent controls, followed by statistical evaluation of the relationship between proteins expressions and patients’ survivals to identify their prognostic values. Cytological experiments with overexpressing or silencing rpS6 by lentivirus in human bronchial epithelial (HBE) and NSCLC cell lines were performed to explore potential mechanisms by which rpS6 affects the clinical development of NSCLC. Additionally, specific RNA interference for Akt1, Akt2, Akt3, Akt inhibitor and subsequent cellular bioactivity tests were employed as well to investigate the upstream regulation of rpS6.ResultsPositive rates of t-rpS6 and p-rpS6 were both significantly increased in NSCLC tissues, compared with controls (82.91 vs 62.20 % for t-rpS6; 52.22 vs 21.95 % for p-rpS6; both P < 0.001). However, only hyperphosphorylation of rpS6, expressed as either elevated p-rpS6 alone or the ratio of p-rpS6 to t-rpS6 (p-rpS6/t-rpS6) no less than 0.67, was greatly associated with the unfavorable survival of NSCLC patients, especially for cases at stage I (all P < 0.001). The independent adverse prognostic value of hyperphosphorylated rpS6 was confirmed by multivariate Cox regression analysis (hazard ratios for elevated p-rpS6 alone and p-rpS6/t-rpS6 no less than 0.67 were 2.403, 4.311 respectively, both P < 0.001). Overexpression or knockdown of rpS6, along with parallel alterations of p-rpS6, led to increased or decreased cells proliferations respectively, which were dependent on redistributions of cell cycles (all P < 0.05). Cells migration and invasion also changed with rpS6 interference (all P < 0.05). Furthermore, upstream overexpression or knockdown of Akt2 or Akt2 phosphorylation inhibition, rather than Akt1 or Akt3, resulted in striking hyperphosphorylation or dephosphorylation of mTOR, p70S6K and rpS6 (all P < 0.05), without any change in total proteins expressions. Further tests showed markedly accompanied variation of cells proliferation, cell cycle distribution and invasion (all P < 0.05).ConclusionHyperphosphorylation of rpS6, probably regulated by the Akt2/mTOR/p70S6K signaling pathway, is closely relevant to the progression of NSCLC and it might be served as a promising therapeutic target for NSCLC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0239-1) contains supplementary material, which is available to authorized users.

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

Cited by 6 publications

References 35 publications

Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms

Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer

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