Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27(Kip1) protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19(ARF) tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19(ARF) 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)(9)-p19(ARF) 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.
Kalinichenko
Vladimir V
VV
University of Illinois at Chicago, College of Medicine, Department of Biochemistry and Molecular Genetics, Chicago, Illinois 60607, USA.
Major
Michael L
ML
Wang
Xinhe
X
Petrovic
Vladimir
V
Kuechle
Joseph
J
Yoder
Helena M
HM
Dennewitz
Margaret B
MB
Shin
Brian
B
Datta
Abhishek
A
Raychaudhuri
Pradip
P
Costa
Robert H
RH
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003114:Colony-Forming Units Assay; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000502:physiology; D018450:Disease Progression; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005136:Eye Proteins; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D019942:Genes, p16; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D051597:Hippocalcin; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008074:Lipoproteins; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D051603:Recoverin; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism
D000477:Alkylating Agents; D002135:Calcium-Binding Proteins; C493961:Cdkn1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D005136:Eye Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D007527:Isoenzymes; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C496731:RCVRN protein, human; C496732:Rcvrn protein, mouse; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D051603:Recoverin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051597:Hippocalcin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases