Down-regulation of HLA class I antigens in prostate cancer tissues and up-regulation by histone deacetylase inhibition.
OBJECTIVE
HLA class I down-regulation in cancer cells confers immunological escape from cytotoxic T lymphocytes. We assessed the frequency of down-regulation of HLA class I antigens in a large series of prostate cancer tissues and determined the mechanism of up-regulation by investigating prostate cancer cell lines.


METHODS
Immunohistochemical staining for HLA class I was done in specimens of 419 prostate cancers. We also investigated clinicopathological parameters, and the relationships between HLA class I down-regulation and the parameters. Furthermore, we examined whether HLA down-regulation was caused by epigenetic changes in vitro.


RESULTS
HLA class I was down-regulated in 311 prostate cancers (74.2%) and it significantly correlated with beta2-microglobulin down-regulation and a higher clinical stage. Flow cytometric analysis revealed a low level of HLA class I in LNCaP cells, which was up-regulated by the histone deacetylase inhibitor trichostatin A (Sigma). Trichostatin A up-regulated LNCaP beta2-microglobulin at the protein level. Furthermore, chromatin immunoprecipitation assay using an anti-acetylated histone H3 antibody provided direct evidence that trichostatin A up-regulated beta2-microglobulin by modulating the acetylation status of the promoter region in LNCaP cells.


CONCLUSIONS
The current study shows that the prevalence of HLA class I down-regulation is high in prostate cancer but histone deacetylase inhibitors can up-regulate HLA class I in LNCaP cells by up-regulating beta2-microglobulin. We suggest that the combination of an immunotherapeutic approach and histone deacetylase inhibition would accentuate the effects of current immunotherapies for prostate cancer.
Kitamura
Hiroshi
H
Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan. hkitamu@sapmed.ac.jp
Torigoe
Toshihiko
T
Asanuma
Hiroko
H
Honma
Ichiya
I
Sato
Noriyuki
N
Tsukamoto
Taiji
T
D000230:Adenocarcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D001613:beta 2-Microglobulin / Q000378:metabolism
D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D001613:beta 2-Microglobulin; C012589:trichostatin A