title: Histone deacetylase inhibition increases levels of choline kinase α and phosphocholine facilitating noninvasive imaging in human cancers.
abstract: Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by (1)H and (31)P MRS in prostate and colon carcinoma cells. In addition, (1)H MRS showed an increase in branched chain amino acid and alanine concentrations. (13)C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase α expression. Furthermore, metabolic labeling experiments with (13)C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester (including PC)/total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate noninvasive imaging biomarker for monitoring the action of HDAC inhibitors.
authors.affiliation: Cancer Research UK and EPSRC Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Mounia
authors.initials: M
authors.lastname: Beloueche-Babari
authors.forename: Vaitha
authors.initials: V
authors.lastname: Arunan
authors.forename: Helen
authors.initials: H
authors.lastname: Troy
authors.forename: Robert H
authors.initials: RH
authors.lastname: te Poele
authors.forename: Anne-Christine Wong
authors.initials: AC
authors.lastname: te Fong
authors.forename: L Elizabeth
authors.initials: LE
authors.lastname: Jackson
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Payne
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
authors.forename: Ian R
authors.initials: IR
authors.lastname: Judson
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D002797:Choline Kinase / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010767:Phosphorylcholine / Q000032:analysis* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013449:Sulfonamides; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D010767:Phosphorylcholine; D002797:Choline Kinase; C487081:belinostat