Comparative effects of histone deacetylase inhibitors on p53 target gene expression, cell cycle and apoptosis in MCF-7 breast cancer cells.

Abstract

Histone deacetylase inhibitors are currently being evaluated for their therapeutic potential and have shown considerable promise as adjuvant therapies for a number of cancers. This study compared the effects of 2 hydroxamic acid based inhibitors, CG-1521 and SAHA, on gene expression, cell cycle and cell death in MCF-7 human breast cancer cells. Both compounds show a dose- and time-dependent effect on cell number (evaluated using crystal violet), however CG-1521 exerts its effects significantly earlier than SAHA, and CG-1521 induces apoptosis (assessed by Apo-BrdU staining and flow cytometry) more rapidly than SAHA. qPCR of cell cycle regulatory and apoptotic genes shows that CG-1521 and SAHA modulate similar cohorts of p53-responsive genes, however, the levels of induction and the timing of the induction differs significantly between the 2 inhibitors. In particular SAHA downregulates cell cycle-associated genes that modulate the G1/S transition (including cyclin D1 and cdc25a) and the G2/M transition [cyclin B1, Plk1, Stk6 (serine-threonine kinase 6, Aurora kinase A) and Kntc2] more significantly than CG-1521. In contrast, CG-1521 significantly induces the expression of several p53 target genes associated with apoptosis including Bnip3/Bnip3L, p21/p21B and Gdf15. The differential levels of gene induction provide molecular evidence of both cell cycle arrest and apoptosis, and suggest a molecular mechanism that explains the difference in the biological effects of the 2 histone deacetylase inhibitors.

• Authors: Andrew Kekapa'a Knutson, Jennifer Welsh, Travis Taylor, Somdutta Roy, Wei-Lin Winnie Wang, Martin Tenniswood
• Journal: Oncology reports (Oncol Rep) Vol. 27 Issue 3 Pg. 849-53 (Mar 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22159450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-phenyl-2,4,6-heptatrienoylhydroxamic acid
• Antineoplastic Agents
• Cell Cycle Proteins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• TP53 protein, human
• Tumor Suppressor Protein p53
• Vorinostat

Topics

• Antineoplastic Agents
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Centrosome (metabolism)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, p53 (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Spindle Apparatus (drug effects, genetics, metabolism)
• Tumor Suppressor Protein p53 (biosynthesis, genetics)
• Vorinostat