Abstract
Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-x(L) antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat.
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Biphenyl Compounds / pharmacology*
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / pharmacology*
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Indoles
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Lymphoma, T-Cell, Cutaneous / genetics
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Lymphoma, T-Cell, Cutaneous / metabolism*
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Lymphoma, T-Cell, Cutaneous / pathology*
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Mice
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Mice, Nude
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Mitochondria / drug effects
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Mitochondria / metabolism
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Nitrophenols / pharmacology*
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Panobinostat
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Piperazines / pharmacology
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA Interference
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism*
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Substrate Specificity
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Sulfonamides / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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ABT-737
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Antineoplastic Agents
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Biphenyl Compounds
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DNA-Binding Proteins
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Hydroxamic Acids
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Indoles
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Membrane Transport Proteins
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NR4A1 protein, human
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Nitrophenols
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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OSCP1 protein, human
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Steroid
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Sulfonamides
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Panobinostat
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HDAC7 protein, human
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Hdac7 protein, mouse
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Histone Deacetylases