The IGF-axis in liver disease : modulation of expression by histone deacetylase inhibitors

The Insulin-like growth factor (IGF) axis is composed of a family of ligands, receptors and binding proteins with important functions in the regulation of cell growth, apoptosis, survival, migration and development. The liver is a major provider of several of the IGF-axis members. Alterations to this axis may therefore be of importance in liver tumorigenesis.

Enzymes that affect chromatin structure are increasingly being implicated in gene expression. One such group of enzymes are those which affect the acetylation status of the chromatin, histone acetyltransferases and histone deacetylases (HATs and HDACs respectively). The interplay between these enzymes is one of the means by which the cell can control gene transcription. The importance of these enzymes in the control of many cellular processes is only just being elucidated but the activities of these enzymes have been found to be important in transcription, cell cycle progression, gene silencing, lymphocyte and muscle differentiation, DNA replication and the cellular response to DNA damage. The role of histone deactylases in the regulation of gene expression can be examined experimentally using specific inhibitors, one of which is trichostatin A.

This thesis is based on studies of the IGF-axis in both primary tumors and experimental manipulation of the axis by histone deacetylase inhibitors in an in vitro cell culture model. An examination of the gene expression profile for IGF-axis members in a series of hepatoblastomas (a pediatric liver tumor), reveals that the expression of many members of this axis are altered in liver tumors. Further investigations reveal that the expression of several important regulatory genes including histone deacetylases are also altered in these tumors. Investigations into the use of the histone deacetylase inhibitor trichostatin A (TSA) in a cell culture system revealed that the effect of this drug is dependent upon cell density. TSA was shown to affect the expression of members of the IGF-axis, in particular the expression of IGF2 and IGFBP-3. Expression of several important cell growth and regulatory genes, including p2l, p27 and TGFß1 were shown to be altered in this cell system upon treatment with TSA. Providing exogenous IGF2 peptide (IGF-II) could modulate the observed effects even further. It was also shown that IGF-II in the presence of IL-2 could affect TSA induced upregulation of HDAC1 mRNA expression.

List of scientific papers

I. Gray SG, Eriksson T, Ekström C, Holm S, von Schweinitz D, Kogner P. Sandstedt B, Pietsch T, Ekström TJ (2000). Members of the Insulin-Like-Growth Factor axis show altered gene expression in Hepatoblastomas. Br J Cancer. [Accepted]

II. Gray SG, Hartman W, Kytölä S, Eriksson T, Ekström C, von Schweinitz D, Kogner P, Sandstedt B, Larsson C, Pietsch T, Ektström TJ (2000). Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas. [Manuscript]

III. Gray SG, Ekström TJ (1998). Effects of cell density and trichostatin A on the expression of HDAC1 and p57Kip2 in Hep 3B cells. Biochem Biophys Res Commun. 245(2): 423-7.
https://pubmed.ncbi.nlm.nih.gov/98238653

IV. Gray SG, Yakovleva T, Hartmann W, Tally M, Bakalkin G, Ekström TJ (1999). IGF-II enhances trichostatin A-induced TGFbeta1 and p21(Waf1,Cip1, sdi1) expression in Hep3B cells. Exp Cell Res. 253(2): 618-28.
https://pubmed.ncbi.nlm.nih.gov/20054278

V. Gray SG, Kytola S, Lui WO, Larsson C, Ekström TJ (2000). Modulating IGFBP-3 expression by trichostatin A: potential therapeutic role in the treatment of hepatocellular carcinoma. Int J Mol Med. 5(1): 33-41.
https://pubmed.ncbi.nlm.nih.gov/20070644

VI. Gray SG, Svechnikova I, Hartmann W, Aguilar-Santelises M, Ekström TJ (2000). IGF-II and IL-2 act synergistically to alter HDAC1 expression following treatments with trichostatin A. Cytokine. [Accepted]