Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP

Watanabe, Ken; Okamoto, Kazuo; Yonehara, Shin

doi:10.1038/sj.cdd.4401507

Cited by 94 publications

(71 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others have reported that chemical and genetic inhibition of HDACs leads to decreased expression of FLIP mRNA (36)(37)(38)(39)(40)(41)(42)(43). However, the mechanism by which inhibiting HDACs decreases FLIP expression is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246-56. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Wood

Dalili

Simpson

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…In myocytes, Hopx can also interact with histone deacetylase 2 and recruits it to SRF-Hopx complexes [51]. Interestingly, histone deacetylase inhibitors have been reported to activate apoptotic pathways including Fas-mediated apoptosis [52][53][54][55] and exhibit therapeutic potential in the treatment of cancer [56,57] and inflammatory diseases [58,59]. In skeletal muscle cells, Hopx is expressed as well, but acts independently of SRF and mostly activates transcription of the target genes [60].…”

Section: Discussionmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

View full text Add to dashboard Cite

Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

show abstract

“…29 FK228 also decreases expression of FLICE inhibitory protein (FLIP) in osteosarcoma and leukemic cells. 21,30 Thus, expression of many apoptosis-related molecules could be modified by HDAC inhibitors. However, we found that FK228 treatment did not change Bcl-2 and Bcl-XL expression and barely affected expression of Bid, Bad, Bim and BAX in SAS and HSC2 cells, suggesting their marginal contribution in FK228 or CBHA-induced apoptosis, though we cannot exclude the possibility that they are somehow involved in the event.…”

Section: Discussionmentioning

confidence: 99%

“…18 In contrast, HDAC inhibitors somehow increase degradation of several apoptosis-related proteins, such as p53, bcr-abl and cellular FADD-like interleukin 1-bconverting enzyme (FLICE)-inhibitory protein FLIP. [19][20][21] However, it is unlikely that these molecules play pivotal roles in the broad spectrum of HDAC inhibitor-induced apoptosis. A recent report shows that HDAC inhibitors increase acetylation of Ku70 and abolish its ability to suppress Bax-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis

et al. 2005

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors modify transcription of selected genes and eventually induce apoptosis. However, molecular mechanisms for their proapoptotic activity remain unclear. We here demonstrate that HDAC inhibitors FK228 and CBHA preferentially upregulated the BH3-only protein Bmf in a broad range of cancer cells. In contrast, HDAC1 overexpression distinctly reduced Bmf expression. FK228 induced histones H3 and H4 acetylation at Bmf promoter region, but not at its 3 0 region, suggesting that histone hyperacetylation causes Bmf transcriptional activation. Knockdown of Bmf transcripts rescued cells from FK228 or CBHA-induced cell death, disruption of mitochondrial membrane potential (DWm) and DNA fragmentation. Taken together, FK228 and CBHA activate Bmf transcription by histone hyperacetylation at its promoter region, and inhibition of this action decreased their proapoptotic activity, thereby highlighting a central role of Bmf in HDAC inhibitor-mediated apoptosis.

show abstract

Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP

Cited by 94 publications

References 38 publications

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Persistence of effector memory Th1 cells is regulated by Hopx

Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis

Contact Info

Product

Resources

About