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

Wood, Tabitha E.; Dalili, Shadi; Simpson, Craig D.; Sukhai, Mahadeo A.; Hurren, Rose; Anyiwe, Kika; Mao, Xinliang; Suárez, Fernando; Gronda, Marcela; Eberhard, Yanina; MacLean, Neil; Ketela, Troy; Reed, John C.; Moffat, Jason; Minden, Mark D.; Batey, Robert A.; Schimmer, Aaron D.

doi:10.1158/1535-7163.mct-09-0495

Cited by 56 publications

(34 citation statements)

References 44 publications

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“…In this study, we provide evidence that HDAC6 is a key deacetylase for Ku70 as, in addition to Vorinostat (inhibitor of HDAC1-3, 6 and 8) 15 and Droxinostat (inhibitor of HDAC3, 6 and 8), 14 the HDAC6-specific inhibitor Tubacin 19 potently increased the acetylation of Ku70. Moreover, both Droxinostat and Tubacin also caused rapid FLIP downregulation.…”

Section: Discussionmentioning

confidence: 80%

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Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

et al. 2012

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FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'. Cell Death and Differentiation (2012) 19, 1317-1327 doi:10.1038/cdd.2012 published online 10 February 2012 FLIP is an anti-apoptotic protein that blocks the activation of apoptosis mediated by death receptors, such as Fas, TRAIL receptor 1 (TRAIL-R1/DR4) and TRAIL-R2 (DR5).1 By binding to the adaptor protein FADD, FLIP inhibits apoptosis by blocking the processing and activation of procaspase 8 (FLICE) by death receptor complexes termed DISCs (death-inducing signalling complexes). 2 We previously reported that FLIP inhibits apoptosis induced by chemotherapeutic agents 3 and that high FLIP expression is an independent adverse prognostic biomarker in colorectal cancer (CRC). 4 These and other studies have indicated that inhibition of FLIP constitutes a promising therapeutic strategy for the treatment of CRC. Ku70 and its binding partner Ku80 are critical components of the non-homologous end joining (NHEJ) DNA repair machinery.5 Ku70 is regulated by acetylation, which is mediated by the histone acetyl transferases (HATs); CREBbinding protein (CBP) and PCAF, and its acetylation can be enhanced by treating cells with histone deacetylase (HDAC) inhibitors.6 Ku70 acetylation disrupts its DNA-binding activity and sensitises cells to DNA-damaging agents. 7 In addition, cytoplasmic Ku70 binds to and regulates the pro-apoptotic Bcl-2 family member, Bax.6 Ku70 simultaneously inhibits Bax degradation via the ubiquitin proteasome system (UPS) and prevents its translocation to the mitochondria. 8 Moreover, it has been reported that Ku70 may have intrinsic deubiquitinating (DUB) activity.8 The Ku70-Bax complex is disrupted by Ku70 acetylation, which promotes Bax translocation to mitochondria and apoptosis induction. Herein, we report a novel interaction between FLIP and Ku70 that regulates FLIP stability. This interaction is acetylation-dependant and is disrupted by HDAC inhibitors with activity against HDAC6. Disruption of the Ku70-FLIP interaction subsequently leads to FLIP degradation by the UPS and induction of c...

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Section: Discussionmentioning

confidence: 80%

“…To identify the HDACs involved in regulating Ku70 acetylation, we used the HDAC inhibitor Droxinostat, 14 which, although less potent, has a more restricted activity than SAHA: Droxinostat is an inhibitor of HDACs 6 and 8, and (to a lesser extent) HDAC3; 14 SAHA inhibits HDACs 1, 2, 3, 6 and (to a lesser extent) 8.…”

Section: Resultsmentioning

confidence: 99%

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

et al. 2012

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“…HDAC8 has been well studied and thus was used as a prototype of HDACs (8,38). The results suggested that CQ was well docked into the active pocket of HDAC8 (Fig.…”

Section: Effects Of Clioquinol On Expression Of Histone Deacetylases-mentioning

confidence: 94%

The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

Cao

Zhu

et al. 2013

Journal of Biological Chemistry

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Background: Clioquinol is a potent chelator of divalent metal ions including zinc. Results: Clioquinol fits the zinc-centered active pocket of HDACs and inhibits HDAC activity, which results in cell cycle arrest and cancer cell apoptosis. Conclusion: Clioquinol inhibits HDAC activity and induces blood cancer cell death. Significance: This is the first report to demonstrate that clioquinol inhibits HDAC activity.

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“…Interference with protein turnover or receptor trafficking, e.g. by application of proteasome inhibitors like bortezomib or protein deacetylase inhibitors, has been shown to increase either death receptor availability or to decrease the availability and function of inhibitory molecules like cellular FLICE-inhibitory protein [118,119,120,121,122]. …”

Section: Novel Compounds Enhancing Cell Death Responsesmentioning

confidence: 99%

Apoptosis-Modulating Drugs for Improved Cancer Therapy

Ocker

Höpfner

2012

Eur Surg Res

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Resistance to cell death induction has been recognized as a hallmark of cancer. Increasing understanding of the underlying molecular events regulating different cell death mechanisms like apoptosis, endoplasmic reticulum stress, autophagy, necroptosis and others has opened new possibilities for targeted interference with these pathways. While conventional chemotherapeutic agents usually inhibit cell cycle progression, DNA replication or mitosis execution, novel agents like small molecule kinase inhibitors also target survival-related kinases and signaling pathways and contribute to overcome resistance to chemotherapy and apoptosis. Additionally, antibodies targeting cellular death receptors have been described to specifically target tumor cells only. This review briefly highlights the pathways involved in (apoptotic) cell death and summarizes the current state of development of specific modulators of cell death and how they can help to improve the tolerability of chemotherapy regimens and increase survival rates in patients with advanced cancer diseases.

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

Cited by 56 publications

References 44 publications

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis

The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

Apoptosis-Modulating Drugs for Improved Cancer Therapy

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