TitleHDAC8 and STAT3 repress BMF gene activity in colon cancer cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsKang, Y, Nian, H, Rajendran, P, Kim, E, Dashwood, WM, Pinto, JT, Boardman, LA, Thibodeau, SN, Limburg, PJ, Löhr, CV, Bisson, WH, Williams, DE, Ho, E, Dashwood, RH
JournalCell Death Dis
Volume5
Paginatione1476
Date Published2014 Oct 16
ISSN2041-4889
KeywordsAdaptor Proteins, Signal Transducing, Apoptosis, Colonic Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, E1A-Associated p300 Protein, HCT116 Cells, Histone Deacetylases, Humans, Models, Biological, Pyruvates, Repressor Proteins, STAT3 Transcription Factor, Transcription, Genetic
Abstract

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.

DOI10.1038/cddis.2014.422
Alternate JournalCell Death Dis
PubMed ID25321483
PubMed Central IDPMC4237248
Grant ListCA122959 / CA / NCI NIH HHS / United States
CA111842 / CA / NCI NIH HHS / United States
P01 CA090890 / CA / NCI NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
R01 CA111842 / CA / NCI NIH HHS / United States
CA090890 / CA / NCI NIH HHS / United States
CA90176 / CA / NCI NIH HHS / United States
P30 ES023512 / ES / NIEHS NIH HHS / United States
R01 CA122959 / CA / NCI NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States