HDAC8 and STAT3 repress BMF gene activity in colon cancer cells Public Deposited

http://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.
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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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  • description.provenance : Made available in DSpace on 2014-12-23T20:32:31Z (GMT). No. of bitstreams: 3 license_rdf: 1370 bytes, checksum: cd1af5ab51bcc7a5280cf305303530e9 (MD5) KangYukiLPIHDAC8STAT3Repress.pdf: 1454363 bytes, checksum: e00f09f70fc98c9284da3fbcee414093 (MD5) KangYukiLPIHDAC8STAT3Repress_SupplementaryMaterials.zip: 1498784 bytes, checksum: f0c2e36b5cbcb6b56c13193456bb18e0 (MD5) Previous issue date: 2014-10
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