title: Essential role of HDAC6 in the regulation of PD-L1 in melanoma.
abstract: Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check-point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immuno-modulatory agents in cancer.
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Lienlaf
authors.initials: L
authors.lastname: M
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Perez-Villarroel
authors.initials: PV
authors.lastname: P
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Knox
authors.initials: K
authors.lastname: T
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Pabon
authors.initials: P
authors.lastname: M
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Sahakian
authors.initials: S
authors.lastname: E
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Powers
authors.initials: P
authors.lastname: J
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Woan
authors.initials: W
authors.lastname: K V
authors.affiliation: All Children's Hospital, Johns Hopkins Medicine, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Lee
authors.initials: L
authors.lastname: C
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Cheng
authors.initials: C
authors.lastname: F
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Deng
authors.initials: D
authors.lastname: S
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Smalley K S
authors.initials: SKS
authors.lastname: M
authors.affiliation: Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Montecino
authors.initials: M
authors.lastname: M
authors.affiliation: University of Illinois at Chicago.
authors.forename: Kozikowski
authors.initials: K
authors.lastname: A
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Pinilla-Ibarz
authors.initials: PI
authors.lastname: J
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Sarnaik
authors.initials: S
authors.lastname: A
authors.affiliation: George Washington University.
authors.forename: Seto
authors.initials: S
authors.lastname: E
authors.affiliation: H. Lee Moffitt Cancer Center, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello.
authors.forename: Weber
authors.initials: W
authors.lastname: J
authors.affiliation: George Washington University.
authors.forename: Sotomayor
authors.initials: S
authors.lastname: E M
authors.affiliation: George Washington University.
authors.forename: Villagra
authors.initials: V
authors.lastname: A
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; D016207:Cytokines; D050796:STAT3 Transcription Factor; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; Histone deacetylases; Melanoma; Nexturastat; PD-L1; PP2A; STAT3; Tubastatin A