title: Translocation of heparanase into nucleus results in cell differentiation.
abstract: We recently reported that heparanase, one of the extracellular matrix-degrading enzymes, which plays a critical role in cancer progression, is located not only in the cytoplasm but also in the nucleus. Here we identified nuclear translocation of heparanase as a key step in cell differentiation. We applied an in vitro differentiation model of HL-60 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA), in which nuclear translocation of heparanase was observed using immunohistochemical analysis. In this system, nuclear translocation of heparanase was abolished by inhibitors of heat shock protein 90 (HSP90), suggesting the involvement of HSP90 in translocation of heparanase. We further confirmed that overexpression of active form of heparanase induced differentiation of HL-60 cells, although the catalytic negative form of heparanase did not. Therefore we speculate that nuclear translocation of enzymatically active heparanase may be involved in cellular differentiation. Our results suggest that a novel function of heparanase upon cell differentiation would raise a potential new strategy for cancer therapy of promyeloid leukemia and other types of cancer.
authors.affiliation: Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Okayama 700-8558, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nobuhisa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Takaomi
authors.initials: T
authors.lastname: Okawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gunduz
authors.forename: Takayuki
authors.initials: T
authors.lastname: Motoki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagatsuka
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tsujigiwa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.forename: Minoru
authors.initials: M
authors.lastname: Haisa
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Junichi
authors.initials: J
authors.lastname: Kurebayashi
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.forename: Jian
authors.initials: J
authors.lastname: Dong
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D021381:Protein Transport; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099175:Heparanase
chemical_list: D016227:Benzoquinones; D005966:Glucuronidase; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D013755:Tetradecanoylphorbol Acetate; D000099175:Heparanase; C001277:geldanamycin