Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma.
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.
Murakami
Takashi
T
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical University, Shimotuke, Tochigi, Japan. takmu@jichi.ac.jp
Sato
Atsuko
A
Chun
Nicole A L
NA
Hara
Mayumi
M
Naito
Yuki
Y
Kobayashi
Yukiko
Y
Kano
Yasuhiko
Y
Ohtsuki
Mamitaro
M
Furukawa
Yusuke
Y
Kobayashi
Eiji
E
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D008545:Melanoma / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D019014:fas Receptor / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D019014:fas Receptor; C087123:romidepsin; D053148:Caspase 3; D053179:Caspase 7; D006655:Histone Deacetylases