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: Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Ikuko Yokota, Ryota Koyama, Masanobu Kusano, Hiromu Suzuki, Masahiro Fujita, Reo Maruyama, Minoru Toyota, Tsuyoshi Saito, Takashi Tokino
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 22 Pg. 7038-47 (Nov 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 22006999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Hydroxamic Acids
• Intercellular Signaling Peptides and Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• hepatoma-derived growth factor
• trichostatin A
• Doxorubicin

Topics

• Cell Line, Tumor
• Cell Movement
• Doxorubicin (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Intercellular Signaling Peptides and Proteins (analysis, genetics, physiology)
• Neoplasm Invasiveness
• Promoter Regions, Genetic
• Tumor Suppressor Protein p53 (physiology)