Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer.
Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetyl...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045539&type=printable |
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| _version_ | 1850224881373806592 |
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| author | Kelly Coffey Timothy J Blackburn Susan Cook Bernard T Golding Roger J Griffin Ian R Hardcastle Lorraine Hewitt Kety Huberman Hesta V McNeill David R Newell Celine Roche Claudia A Ryan-Munden Anna Watson Craig N Robson |
| author_facet | Kelly Coffey Timothy J Blackburn Susan Cook Bernard T Golding Roger J Griffin Ian R Hardcastle Lorraine Hewitt Kety Huberman Hesta V McNeill David R Newell Celine Roche Claudia A Ryan-Munden Anna Watson Craig N Robson |
| author_sort | Kelly Coffey |
| collection | DOAJ |
| description | Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer. |
| format | Article |
| id | doaj-art-ad0f8a29724847c78bbacae4be080277 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-ad0f8a29724847c78bbacae4be0802772025-08-20T02:05:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4553910.1371/journal.pone.0045539Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer.Kelly CoffeyTimothy J BlackburnSusan CookBernard T GoldingRoger J GriffinIan R HardcastleLorraine HewittKety HubermanHesta V McNeillDavid R NewellCeline RocheClaudia A Ryan-MundenAnna WatsonCraig N RobsonTip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045539&type=printable |
| spellingShingle | Kelly Coffey Timothy J Blackburn Susan Cook Bernard T Golding Roger J Griffin Ian R Hardcastle Lorraine Hewitt Kety Huberman Hesta V McNeill David R Newell Celine Roche Claudia A Ryan-Munden Anna Watson Craig N Robson Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS ONE |
| title | Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. |
| title_full | Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. |
| title_fullStr | Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. |
| title_full_unstemmed | Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. |
| title_short | Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. |
| title_sort | characterisation of a tip60 specific inhibitor nu9056 in prostate cancer |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0045539&type=printable |
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