title: p53 negatively regulates the hepatoma growth factor HDGF.
abstract: Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression.
authors: Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.
authors: Yasushi
authors: Y
authors: Sasaki
authors: Hideaki
authors: H
authors: Negishi
authors: Masashi
authors: M
authors: Idogawa
authors: Ikuko
authors: I
authors: Yokota
authors: Ryota
authors: R
authors: Koyama
authors: Masanobu
authors: M
authors: Kusano
authors: Hiromu
authors: H
authors: Suzuki
authors: Masahiro
authors: M
authors: Fujita
authors: Reo
authors: R
authors: Maruyama
authors: Minoru
authors: M
authors: Toyota
authors: Tsuyoshi
authors: T
authors: Saito
authors: Takashi
authors: T
authors: Tokino
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C051610:hepatoma-derived growth factor; C012589:trichostatin A; D004317:Doxorubicin