Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation.
Breast cancer encompasses a heterogeneous group of diseases at the molecular level. It is known that chemosensitivity of breast cancer depends on its molecular subtype. We investigated the growth inhibitory effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, and the mechanism of this inhibition on four breast cancer cell lines with different molecular subtypes. The growth inhibitory effect of VPA in the four different breast cancer cell lines was investigated. The alteration of levels of p21 WAF1, cleaved caspase-3, acetylated Heat shock protein (Hsp) 90, acetylated Hsp70, and acetylated α-tubulin by VPA was examined in VPA-sensitive, human epidermal receptor 2 (HER2)-overexpressing SKBR3 cells. The cell growth inhibition of breast cancer cell lines was dependent on the dose and exposure time of VPA. The cell growth of HER2-overexpressing SKBR3 cell line was inhibited by VPA to a much greater degree than other cell lines studied. In SKBR3 cell line, VPA upregulated expression of p21 WAF1 and cleaved caspase-3 in the early phase. VPA markedly increased Hsp70 acetylation in a time-dependent manner but did not increase Hsp90 acetylation. Our data demonstrated that VPA inhibited cell proliferation and induced cell cycle arrest and apoptosis of HER2-overexpressing breast cancer cells. This anti-proliferation effect might be the direct function of VPA as an HDAC inhibitor. We propose an alternative mechanism whereby acetylation of Hsp70 disrupts the function of Hsp90 and leads to downregulation of its client proteins, including HER2 that might be the indirect function of VPA, in the sense that non-histone proteins are acetylated.
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Toshiki
T
Mawatari
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Itasu
I
Ninomiya
Breast Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Masafumi
M
Inokuchi
Center for Biomedical Research and Education, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Shinichi
S
Harada
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Hironori
H
Hayashi
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Katsunobu
K
Oyama
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Isamu
I
Makino
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Hisatoshi
H
Nakagawara
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Tomoharu
T
Miyashita
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Hidehiro
H
Tajima
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Hiroyuki
H
Takamura
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Sachio
S
Fushida
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Tetsuo
T
Ohta
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D014635:Valproic Acid; C508053:ERBB2 protein, human