Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth.
We identified the far upstream element binding protein 1 (FBP1), an activator of transcription of the proto-oncogene c-myc, in a functional yeast survival screen for tumor-related antiapoptotic proteins and demonstrated strong overexpression of FBP1 in human hepatocellular carcinoma (HCC). Knockdown of the protein in HCC cells resulted in increased sensitivity to apoptotic stimuli, reduced cell proliferation, and impaired tumor formation in a mouse xenograft transplantation model. Interestingly, analysis of gene regulation in these cells revealed that c-myc levels were not influenced by FBP1 in HCC cells. Instead, we identified the cell cycle inhibitor p21 as a direct target gene repressed by FBP1, and in addition, expression levels of the proapoptotic genes tumor necrosis factor alpha, tumor necrosis factor-related apoptosis-inducing ligand, Noxa, and Bik were elevated in the absence of FBP1.


CONCLUSIONS
Our data establish FBP1 as an important oncoprotein overexpressed in HCC that induces tumor propagation through direct or indirect repression of cell cycle inhibitors and proapoptotic target genes.
Rabenhorst
Uta
U
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt, Germany.
Beinoraviciute-Kellner
Rasa
R
Brezniceanu
Marie-Luise
ML
Joos
Stefan
S
Devens
Frauke
F
Lichter
Peter
P
Rieker
Ralf J
RJ
Trojan
Jörg
J
Chung
Hye-Jung
HJ
Levens
David L
DL
Zörnig
Martin
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D004265:DNA Helicases