Cargando…

HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic...

Descripción completa

Detalles Bibliográficos
Autores principales: Kang, Y, Nian, H, Rajendran, P, Kim, E, Dashwood, W M, Pinto, J T, Boardman, L A, Thibodeau, S N, Limburg, P J, Löhr, C V, Bisson, W H, Williams, D E, Ho, E, Dashwood, R H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237248/
https://www.ncbi.nlm.nih.gov/pubmed/25321483
http://dx.doi.org/10.1038/cddis.2014.422
_version_ 1782345314681749504
author Kang, Y
Nian, H
Rajendran, P
Kim, E
Dashwood, W M
Pinto, J T
Boardman, L A
Thibodeau, S N
Limburg, P J
Löhr, C V
Bisson, W H
Williams, D E
Ho, E
Dashwood, R H
author_facet Kang, Y
Nian, H
Rajendran, P
Kim, E
Dashwood, W M
Pinto, J T
Boardman, L A
Thibodeau, S N
Limburg, P J
Löhr, C V
Bisson, W H
Williams, D E
Ho, E
Dashwood, R H
author_sort Kang, Y
collection PubMed
description Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy.
format Online
Article
Text
id pubmed-4237248
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-42372482014-11-26 HDAC8 and STAT3 repress BMF gene activity in colon cancer cells Kang, Y Nian, H Rajendran, P Kim, E Dashwood, W M Pinto, J T Boardman, L A Thibodeau, S N Limburg, P J Löhr, C V Bisson, W H Williams, D E Ho, E Dashwood, R H Cell Death Dis Original Article Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to identify a direct target gene of HDAC8 repression, namely, BMF. Interestingly, the repressive role of HDAC8 could be uncoupled from HDAC1 to trigger Bmf-mediated apoptosis. These findings have implications for the development of HDAC8-selective inhibitors as therapeutic agents, beyond the reported involvement of HDAC8 in childhood malignancy. Nature Publishing Group 2014-10 2014-10-16 /pmc/articles/PMC4237248/ /pubmed/25321483 http://dx.doi.org/10.1038/cddis.2014.422 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Kang, Y
Nian, H
Rajendran, P
Kim, E
Dashwood, W M
Pinto, J T
Boardman, L A
Thibodeau, S N
Limburg, P J
Löhr, C V
Bisson, W H
Williams, D E
Ho, E
Dashwood, R H
HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title_full HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title_fullStr HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title_full_unstemmed HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title_short HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
title_sort hdac8 and stat3 repress bmf gene activity in colon cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237248/
https://www.ncbi.nlm.nih.gov/pubmed/25321483
http://dx.doi.org/10.1038/cddis.2014.422
work_keys_str_mv AT kangy hdac8andstat3repressbmfgeneactivityincoloncancercells
AT nianh hdac8andstat3repressbmfgeneactivityincoloncancercells
AT rajendranp hdac8andstat3repressbmfgeneactivityincoloncancercells
AT kime hdac8andstat3repressbmfgeneactivityincoloncancercells
AT dashwoodwm hdac8andstat3repressbmfgeneactivityincoloncancercells
AT pintojt hdac8andstat3repressbmfgeneactivityincoloncancercells
AT boardmanla hdac8andstat3repressbmfgeneactivityincoloncancercells
AT thibodeausn hdac8andstat3repressbmfgeneactivityincoloncancercells
AT limburgpj hdac8andstat3repressbmfgeneactivityincoloncancercells
AT lohrcv hdac8andstat3repressbmfgeneactivityincoloncancercells
AT bissonwh hdac8andstat3repressbmfgeneactivityincoloncancercells
AT williamsde hdac8andstat3repressbmfgeneactivityincoloncancercells
AT hoe hdac8andstat3repressbmfgeneactivityincoloncancercells
AT dashwoodrh hdac8andstat3repressbmfgeneactivityincoloncancercells