HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

• Published in: Cell death & disease 2014-10, Vol.5 (10), p.e1476-e1476
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/2; 38/77; 38/89; 42/109; 631/208/2489/2487/2486; 631/67/1504/1885/1393; 631/80/82/23; 82/1; 82/80; 96/106; Adaptor Proteins, Signal Transducing - genetics; Antibodies; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; E1A-Associated p300 Protein - metabolism; HCT116 Cells; Histone Deacetylases - metabolism; Humans; Immunology; Life Sciences; Models, Biological; Original; original-article; Pyruvates - pharmacology; Repressor Proteins - metabolism; STAT3 Transcription Factor - metabolism; Transcription, Genetic - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.422

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.