title: Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics.
abstract: Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA. liquenti@mail.nih.gov.
authors.forename: Qingdi Quentin
authors.initials: QQ
authors.lastname: Li
authors.affiliation: Poochon Scientific, Frederick, Maryland, 21701, USA.
authors.forename: Jian-Jiang
authors.initials: JJ
authors.lastname: Hao
authors.affiliation: Poochon Scientific, Frederick, Maryland, 21701, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: L Spencer
authors.initials: LS
authors.lastname: Krane
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Kai H
authors.initials: KH
authors.lastname: Hammerich
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sanford
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA. trepelj@mail.nih.gov.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA. agarwalpk2@mail.nih.gov.
authors.forename: Piyush K
authors.initials: PK
authors.lastname: Agarwal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods*; D012118:Resorcinols / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D001549:Benzamides; D052117:Benzodioxoles; C543177:CUDC 305; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D006657:Histones; D007093:Imidazoles; D054833:Isoindoles; D007555:Isoxazoles; D012118:Resorcinols; C534922:SNX 2112; C533237:STA 9090; D014230:Triazoles; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone