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HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

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https://ir.library.oregonstate.edu/concern/articles/w6634527g

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  • 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.
  • This is the publisher’s final pdf. The published article is copyrighted by Macmillan Publishers Limited and can be found at: http://www.nature.com/cddis/index.html.
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  • Kang, Y., Nian, H., Rajendran, P., Kim, E., Dashwood, W. M., Pinto, J. T., ... & Dashwood, R. H. (2014). HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell Death & Disease, 5, e1476. doi:10.1038/cddis.2014.422
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  • 5
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  • This work was supported by NIH grants CA090890, CA122959, CA90176, CA111842, P30 ES00210, P30 ES023512, and a Chancellor’s Research Initiative from Texas A&M University.
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