title: HAMLET interacts with histones and chromatin in tumor cell nuclei.
abstract: HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.
authors.affiliation: Institute of Laboratory Medicine, Section for Microbiology, Immunology and Glycobiology, Lund University, Sölvegatan 23, 223 62 Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Düringer
authors.forename: Ali
authors.initials: A
authors.lastname: Hamiche
authors.forename: Lotta
authors.initials: L
authors.lastname: Gustafsson
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D011232:Chemical Precipitation; D002843:Chromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007768:Lactalbumin / Q000378:metabolism* / Q000493:pharmacokinetics; D019301:Oleic Acid; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D019301:Oleic Acid; D007768:Lactalbumin