HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Academic Article uri icon

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--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.

published proceedings

  • Cell Death Dis

altmetric score

  • 7

author list (cited authors)

  • Kang, Y., Nian, H., Rajendran, P., Kim, E., Dashwood, W. M., Pinto, J. T., ... Dashwood, R. H.

citation count

  • 50

complete list of authors

  • Kang, 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

publication date

  • October 2014