Keynote review: Chromatin control and cancer-drug discovery: realizing the promise

Inche, A; Thangué, Nicholas B. La

doi:10.1016/s1359-6446(05)03691-3

Cited by 75 publications

(69 citation statements)

References 145 publications

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“…In the current study, class I HDACs were highly expressed in many cancer tissues, but we consider that there are not so many cancer tissues in which class I HDACs are more expressed than the normal epithelium. The activity of class I HDACs is due to histone acetylation status, and HDAC complexes are related to this status (30), therefore, more detailed study, including the expression status of the HDAC complex, is required to predict the effectiveness of HDAC inhibitors. When HDAC inhibitors are used as anti-cancer agents, adjuvant administration should be conbined to avoid side effects, because in many cancers, class I HDACs are overexpressed in cancer and non-cancerous tissues.…”

Section: Discussionmentioning

confidence: 99%

Expression profile of class I histone deacetylases in human cancer tissues

Nakagawa

Oda²,

Eguchi³

et al. 2007

Oncol Rep

214

218

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Abstract. Histone deacetylase (HDAC) activity is one of the widely used and well-established mechanisms for regulation of various genes in cancer. To identify which subtype of class I HDACs are overexpressed in cancers, we analyzed the expression of class I HDAC isotypes composed of HDAC1, 2, 3 and 8 in several cell lines and human cancer tissues, including cancer of the stomach, esophagus, colon, prostate, breast, ovary, lung, pancreas and thyroid. The results showed that >75% of human cancer tissues and their corresponding non-cancerous epithelium showed high expression of these class I HDACs. However, the immunoreactivity of HDAC8 in both prostatic cancer tissue and non-cancerous prostate glands was lower than that in other cancer tissues. Furthermore, 5-40% of cancer tissues overexpressed class I HDACs, when compared with normal epithelium. The results suggest the potential usefulness of HDAC inhibitors for the treatment of a wide variety of human cancers.

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Section: Discussionmentioning

confidence: 99%

Expression profile of class I histone deacetylases in human cancer tissues

Nakagawa

Oda²,

Eguchi³

et al. 2007

Oncol Rep

214

218

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“…1 An increasingly large group of proteins connected with different aspects of normal and tumour cell biology are known to be influenced by acetylation. [2][3][4] As a consequence, the HDAC family has attracted considerable attention as a therapeutic target.…”

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confidence: 99%

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

et al. 2013

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Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment. Cell Death and Differentiation (2013) 20, 1306-1316 doi:10.1038/cdd.2013 published online 24 May 2013 Histone deacetylase is a family of enzymes that control the acetylation of chromatin.1 An increasingly large group of proteins connected with different aspects of normal and tumour cell biology are known to be influenced by acetylation.2-4 As a consequence, the HDAC family has attracted considerable attention as a therapeutic target.2,3,5 Indeed, inhibition of HDAC activity is strongly anti-proliferative on tumour cells in vitro, and delays tumour growth in xenograft models. [5][6][7] An extensive number of clinical trials with HDAC inhibitors in a variety of malignancies are underway, and two HDAC inhibitors, SAHA/Vorinostat and FK228/Romidepsin, have to date been approved for treating a human malignancy, namely cutaneous T-cell lymphoma (CTCL 1,(8)(9)(10) ). However, identifying other malignancies and disease types that are likely to respond favourably to HDAC inhibitors has been hampered, principally because knowledge of the key pathways through which HDAC inhibitors affect tumour cell growth remains limited. 9,11 In previous studies, we undertook through a genome-wide loss-of-function screen to identify genes that have an impact on the sensitivity of tumour cells to HDAC inhibitors. 12 We reasoned that genes identified in this way would not only provide important information on key pathways affected by HDAC inhibitors, but also identify potential biomarkers that inform on the tumour response to HDAC inhibitor-based therapies. 11,12 Through this analysis, we identified HR23B as a protein that influences the response and sensitivity of tumour cells to HDAC inhibitors.12 HR23B functions in at least two pathways; nucleotide excision repair (NER) and protein targeting to the proteasome. [13][14][15] Further studies suggested that the ability of HR23B to engage in proteasomal shuttling underpins its role as a determinant of HDAC inhibitor sensitivity, and it is consistent with this idea that aberrant proteasome activity occurs in tumour cells trea...

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“…Aberrant epigenetic control is an early event in the onset of tumor progression, and there have been intense efforts to develop drugs that modulate epigenesis in cancer (2). One of the most promising approaches has been seen in the development of inhibitors of histone deacetylase (HDAC).…”

mentioning

confidence: 99%

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

Khan

Fotheringham

Wood

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

138

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Histone deacetylase (HDAC) inhibitors are emergent cancer drugs. HR23B is a candidate cancer biomarker identified in a genome-wide loss-of-function screen which influences sensitivity to HDAC inhibitors. Because HDAC inhibitors have found clinical utility in cutaneous T-cell lymphoma (CTCL), we evaluated the role of HR23B in CTCL cells. Our results show that HR23B governs the sensitivity of CTCL cells to HDAC inhibitors. Furthermore, proteasome activity is deregulated in HDAC inhibitor-treated CTCL cells through a mechanism dependent upon HR23B, and HDAC inhibitors sensitize CTCL cells to the effects of proteasome inhibitors. The predictive power of HR23B for clinical response to HDAC inhibitors was investigated through an analysis of a unique collection of CTCL biopsies taken from a phase II clinical trial, where there was a frequent coincidence between HR23B expression and clinical response to HDAC inhibitor. Our study supports the personalized medicine approach for treating cancer and the increasing drive to translate laboratory-based findings into clinical utility.cancer | histone deacetylase inhibitor | biomarker | proteasome | clinical trial I t is widely recognized that one of the most significant hurdles to developing new and efficacious cancer drugs is the absence of proven strategies that enable responsive tumors to be identified and treated with the most effective drug. Predictive biomarkers that inform on the clinical response to cancer therapies will not only assist in planning focused and hypothesis-driven clinical development programs but, once approved, provide a companion biomarker that enables patients to be stratified and aligned with an appropriate therapeutic regime (1).Aberrant epigenetic control is an early event in the onset of tumor progression, and there have been intense efforts to develop drugs that modulate epigenesis in cancer (2). One of the most promising approaches has been seen in the development of inhibitors of histone deacetylase (HDAC). HDAC is a family of enzymes that regulate the acetylation level of chromatin, together with a variety of nonhistone proteins (3). Proteins that are involved with tumor progression, including the cell cycle, apoptosis, angiogenesis, and cell invasion, are influenced by acetylation (4).HDAC inhibitors are potent antiproliferative agents in cellbased studies, where they exhibit striking effects on tumor cell proliferation (5-7). Consequently, there has been great interest in developing HDAC inhibitors as new anticancer agents, and an extensive number of clinical trials are underway in which HDAC inhibitors either alone or in combination with other agents are being evaluated (8). To date, SAHA (also known as Vorinostat and Zolinza) and more recently romidepsin (also known as depsipeptide, FK228, and Istodax) are the only HDAC inhibitorbased therapies that have achieved regulatory approval, being marketed for the treatment of advanced and refractory cutaneous T-cell lymphoma (CTCL) (9-11) (http://istodax.com) . Other than CTCL, tumor types that ha...

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Keynote review: Chromatin control and cancer-drug discovery: realizing the promise

Cited by 75 publications

References 145 publications

Expression profile of class I histone deacetylases in human cancer tissues

Expression profile of class I histone deacetylases in human cancer tissues

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

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