title: Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation.
abstract: The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: K V
authors.initials: KV
authors.lastname: Woan
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lienlaf
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: P
authors.initials: P
authors.lastname: Perez-Villaroel
authors.affiliation: All Children's Hospital, Johns Hopkins Medicine, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cheng
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: T
authors.initials: T
authors.lastname: Knox
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Woods
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: K
authors.initials: K
authors.lastname: Barrios
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: J
authors.initials: J
authors.lastname: Powers
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sahakian
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: H W
authors.initials: HW
authors.lastname: Wang
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: J
authors.initials: J
authors.lastname: Canales
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: D
authors.initials: D
authors.lastname: Marante
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: K S M
authors.initials: KSM
authors.lastname: Smalley
authors.affiliation: University of Illinois at Chicago, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bergman
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: E
authors.initials: E
authors.lastname: Seto
authors.affiliation: University of Illinois at Chicago, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kozikowski
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sarnaik
authors.affiliation: Georgia Regents University, USA.
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: J
authors.initials: J
authors.lastname: Weber
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Sotomayor
authors.affiliation: H. Lee Moffitt Cancer Center, USA.
authors.forename: A
authors.initials: A
authors.lastname: Villagra
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D056572:Histone Deacetylase Inhibitors; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; Histone deacetylases; Melanoma; Nexturastat; Tubastatin A