Hepatocyte nuclear factor-4-independent synthesis of coagulation factor VII in breast cancer cells and its inhibition by targeting selective histone acetyltransferases.
Tissue factor/coagulation factor VII (fVII) complex formation on the surface of cancer cells plays important roles in cancer biology, such as cell migration and invasion, angiogenesis, and antiapoptotic effects. We recently found that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion. Here, we characterized mechanisms of hepatic and ectopic fVII (FVII) gene expression to identify molecular targets enabling selective inhibition of the ectopic expression. Unlike hepatic expression, hepatocyte nuclear factor-4 binding to the promoter is not required for ectopic FVII expression, although Sp1 binding is essential. Furthermore, we found novel nuclear targets of basal hepatocytic and ectopic FVII expression. Notably, histone acetyltransferases p300 and cyclic AMP-responsive element binding protein-binding protein (CBP) are exclusively recruited to the promoter region of the FVII gene specifically in breast cancer cells. We further show that curcumin, a dietary compound, can selectively inhibit ectopic fVII expression by targeting p300/CBP activity. These results suggest a strategy to inhibit ectopic fVII-induced tumor progression without impairment of the physiologic hemostatic process.
Koizume
Shiro
S
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan.
Yokota
Naho
N
Miyagi
Etsuko
E
Hirahara
Fumiki
F
Nakamura
Yoshiyasu
Y
Sakuma
Yuji
Y
Yoshida
Akira
A
Kameda
Yoichi
Y
Tsuchiya
Eiju
E
Ruf
Wolfram
W
Miyagi
Yohei
Y
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005167:Factor VII / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects
D002843:Chromatin; D004791:Enzyme Inhibitors; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D009363:Neoplasm Proteins; D005167:Factor VII; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; D003474:Curcumin