title: SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis.
abstract: Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs), but has not yet been explored in cutaneous T-cell lymphoma (CTCL). We analyzed five CTCL cell lines and lesional tissues using flow cytometry, immunostaining, immunoblotting, cell death, viability, and apoptosis assays, small-molecule inhibitors, and shRNA knockdown. We found strong SIRT1 expression among CTCL lines relative to normal lymphocytes. CTCL cells in lesional tissues also expressed SIRT1 strongly. SIRT1 knockdown resulted in reduced cellular metabolism and proliferation, increased apoptosis, and PARP cleavage products. Tenovin-1, which reversibly inhibits class III HDACs (SIRT1 and SIRT2), reduced SIRT enzymatic activity and SIRT1 expression and led to increased apoptosis. These alterations were accompanied by increased forkhead box O3 (FoxO3) in several cell lines and increased nuclear p53, as well as acetylated p53 in wtp53 MyLa CTCL line. A combination of class I/II and class III HDACIs (vorinostat and tenovin-1) produced significantly greater growth inhibition, cell death via apoptosis, as well as superior p53 promoter upregulation in wtp53 MyLa cells as compared with either agent alone. This occurred in a partially p53-dependent manner, as these effects were blunted by p53 knockdown. Our results indicate that SIRT1 is strongly expressed in CTCL. Its inhibition results in reduced growth and increased apoptosis of CTCL cells. Furthermore, our findings suggest that some CTCL patients, such as those with wtp53, might benefit more from treatment with a combination of different classes of HDACIs than with a single agent.
authors.affiliation: Department of Dermatology; University of Wisconsin School of Medicine and Public Health; Madison, WI USA; Paul P. Carbone Comprehensive Cancer Center; University of Wisconsin School of Medicine and Public Health; Madison, WI USA.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Nihal
authors.affiliation: Department of Dermatology; University of Wisconsin School of Medicine and Public Health; Madison, WI USA; Paul P. Carbone Comprehensive Cancer Center; University of Wisconsin School of Medicine and Public Health; Madison, WI USA; William S. Middleton Memorial Veterans Hospital; Madison, WI USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Dermatology; University of Wisconsin School of Medicine and Public Health; Madison, WI USA; Paul P. Carbone Comprehensive Cancer Center; University of Wisconsin School of Medicine and Public Health; Madison, WI USA; William S. Middleton Memorial Veterans Hospital; Madison, WI USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wood
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D000077337:Vorinostat
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; C000594735:tenovin-1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases; D013890:Thiourea
keywords: CTCL; HDACI; SIRT1; apoptosis; p53