Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma.

Abstract

With melanoma, as with many other malignancies, aberrant transcriptional repression is a hallmark of refractory cancer. To restore gene expression, use of a histone deacetylase inhibitor (HDACi) is expected to be effective. Our recent DNA micro-array analysis showed that the HDACi depsipeptide (FK228) significantly enhances gp100 antigen expression. Herein, we demonstrate that depsipeptide promotes tumor-specific T-cell-mediated killing of B16/F10 murine melanoma cells. First, by a quantitative assay of caspase-3/7 activity, a sublethal dose of depsipeptide was determined (ED50: 5 nM), in which p21(Waf1/Cip1) and Fas were sufficiently evoked concomitantly with histone H3 acetylation. Second, the sublethal dose of depsipeptide treatment with either a recombinant Fas ligand or tumor-specific T cells synergistically enhanced apoptotic cell death in B16/F10 cells in vitro. Furthermore, we found that depsipeptide increased levels of perforin in T cells. Finally, in vivo metastatic growth of B16/F10 in the lung was significantly inhibited by a combination of depsipeptide treatment and immune cell adoptive transfer from immunized mice using irradiated B16 cells and gp100-specific (Pmel-1) TCR transgenic mice (P<0.05, vs cell transfer alone). Consequently, employment of a transcriptional modulation strategy using HDACis might prove to be a useful pretreatment for human melanoma immunotherapy.

• Authors: Takashi Murakami, Atsuko Sato, Nicole A L Chun, Mayumi Hara, Yuki Naito, Yukiko Kobayashi, Yasuhiko Kano, Mamitaro Ohtsuki, Yusuke Furukawa, Eiji Kobayashi
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 128 Issue 6 Pg. 1506-16 (Jun 2008) ISSN: 1523-1747 [Electronic] United States
• PMID: 18185535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Depsipeptides
• fas Receptor
• romidepsin
• Caspase 3
• Caspase 7
• Histone Deacetylases

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Depsipeptides (pharmacology)
• Gene Expression Regulation, Neoplastic
• Histone Deacetylases (metabolism)
• Melanoma (pathology)
• Melanoma, Experimental
• Mice
• Mice, Transgenic
• Oligonucleotide Array Sequence Analysis
• Transcription, Genetic
• fas Receptor (metabolism)