HDAC8 and STAT3 repress BMF gene activity in colon cancer cells

Y. Kang, H. Nian, P. Rajendran, W. M. Dashwood, J. T. Pinto, Lisa Allyn Boardman, Stephen N Thibodeau, Paul John Limburg, C. V. Löhr, W. H. Bisson, D. E. Williams, E. Ho, R. H. Dashwood

Research output: Contribution to journalArticle

27 Citations (Scopus)

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-a-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.

Original languageEnglish (US)
Article numbere1476
JournalCell Death and Disease
Volume5
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

STAT3 Transcription Factor
Colonic Neoplasms
Histone Deacetylase Inhibitors
Sp3 Transcription Factor
Apoptosis
Genes
Keto Acids
Acetylation
RNA Interference
Antineoplastic Agents
Histones
Clinical Trials
Survival
Therapeutics
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Kang, Y., Nian, H., Rajendran, P., Dashwood, W. M., Pinto, J. T., Boardman, L. A., ... Dashwood, R. H. (2014). HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell Death and Disease, 5(10), [e1476]. https://doi.org/10.1038/cddis.2014.422

HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. / Kang, Y.; Nian, H.; Rajendran, P.; Dashwood, W. M.; Pinto, J. T.; Boardman, Lisa Allyn; Thibodeau, Stephen N; Limburg, Paul John; Löhr, C. V.; Bisson, W. H.; Williams, D. E.; Ho, E.; Dashwood, R. H.

In: Cell Death and Disease, Vol. 5, No. 10, e1476, 01.01.2014.

Research output: Contribution to journalArticle

Kang, Y, Nian, H, Rajendran, P, Dashwood, WM, Pinto, JT, Boardman, LA, Thibodeau, SN, Limburg, PJ, Löhr, CV, Bisson, WH, Williams, DE, Ho, E & Dashwood, RH 2014, 'HDAC8 and STAT3 repress BMF gene activity in colon cancer cells', Cell Death and Disease, vol. 5, no. 10, e1476. https://doi.org/10.1038/cddis.2014.422
Kang, Y. ; Nian, H. ; Rajendran, P. ; Dashwood, W. M. ; Pinto, J. T. ; Boardman, Lisa Allyn ; Thibodeau, Stephen N ; Limburg, Paul John ; Löhr, C. V. ; Bisson, W. H. ; Williams, D. E. ; Ho, E. ; Dashwood, R. H. / HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. In: Cell Death and Disease. 2014 ; Vol. 5, No. 10.
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