title: TLR Adaptor Protein MYD88 Mediates Sensitivity to HDAC Inhibitors via a Cytokine-Dependent Mechanism.
abstract: Histone deacetylase (HDAC) inhibitors have proven useful therapeutic agents for certain hematologic cancers. However, HDAC inhibition causes diverse cellular outcomes, and identification of cancer-relevant pathways within these outcomes remains unresolved. In this study, we utilized an unbiased loss-of-function screen and identified the Toll-like receptor (TLR) adaptor protein MYD88 as a key regulator of the antiproliferative effects of HDAC inhibition. High expression of MYD88 exhibited increased sensitivity to HDAC inhibitors; conversely, low expression coincided with reduced sensitivity. MYD88-dependent TLR signaling controlled cytokine levels, which then acted via an extracellular mechanism to maintain cell proliferation and sensitize cells to HDAC inhibition. MYD88 activity was directly regulated through lysine acetylation and was deacetylated by HDAC6. MYD88 was a component of a wider acetylation signature in the ABC subgroup of diffuse large B-cell lymphoma, and one of the most frequent mutations in MYD88, L265P, conferred increased cell sensitivity to HDAC inhibitors. Our study defines acetylation of MYD88, which, by regulating TLR-dependent signaling to cytokine genes, influences the antiproliferative effects of HDAC inhibitors. Our results provide a possible explanation for the sensitivity of malignancies of hematologic origin to HDAC inhibitor-based therapy. Cancer Res; 76(23); 6975-87. ©2016 AACR.
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: New
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Semira
authors.initials: S
authors.lastname: Sheikh
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Mina
authors.initials: M
authors.lastname: Bekheet
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Heidi
authors.initials: H
authors.lastname: Olzscha
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Marie-Laetitia
authors.initials: ML
authors.lastname: Thezenas
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.|Bioinformatics Group, School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Care
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Fotheringham
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Reuben M
authors.initials: RM
authors.lastname: Tooze
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Department of Oncology, University of Oxford, Oxford, United Kingdom. nick.lathangue@oncology.ox.ac.uk.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: La Thangue
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014162:Transfection
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors