Translocation of heparanase into nucleus results in cell differentiation.
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.
Nobuhisa
Tetsuji
T
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.
Naomoto
Yoshio
Y
Okawa
Takaomi
T
Takaoka
Munenori
M
Gunduz
Mehmet
M
Motoki
Takayuki
T
Nagatsuka
Hitoshi
H
Tsujigiwa
Hidetsugu
H
Shirakawa
Yasuhiro
Y
Yamatsuji
Tomoki
T
Haisa
Minoru
M
Matsuoka
Junji
J
Kurebayashi
Junichi
J
Nakajima
Motowo
M
Taniguchi
Shun'ichiro
S
Sagara
Junji
J
Dong
Jian
J
Tanaka
Noriaki
N
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
D016227:Benzoquinones; D005966:Glucuronidase; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D013755:Tetradecanoylphorbol Acetate; D000099175:Heparanase; C001277:geldanamycin