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Comparative analysis of the effects of histone deacetylase inhibitors on cell cycle and cell death in MCF‐7 breast cancer cells
Author(s) -
Knutson Andrew Kekupa’a,
Taylor Travis,
Welsh Jennifer,
Roy Somdutta,
Tenniswood Martin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.637.3
Subject(s) - apoptosis , cell cycle , mcf 7 , cancer research , histone deacetylase , cyclin d1 , cancer cell , cell growth , biology , cell cycle checkpoint , histone deacetylase inhibitor , cyclin b1 , chemistry , cancer , microbiology and biotechnology , histone , gene , cyclin dependent kinase 1 , biochemistry , human breast , genetics
Histone deacetylase inhibitors (HDIs) are currently being evaluated for their therapeutic potential and have shown considerable promise as a possible adjuvant therapy for many cancer types. Posttranslational modifications of the tumor suppressor protein, p53, stabilize the protein, and affect its downstream target gene activation. This study compared the activity of two HDIs, JW‐1521 and SAHA, on p53+/+ MCF‐7 human breast cancer cells. Crystal violet growth assays of JW‐1521 and SAHA treated cells show differential levels of apoptosis with JW‐1521 having a much earlier and more cytotoxic effect. Flow cytometry confirmed this, showing clear apoptosis in JW‐1521 treated cells (37%) and relatively little apoptosis in SAHA treated cells (4%) after 48 hours. Cell cycle associated genes known to be downstream transcriptional targets of p53, including genes cyclin B1, cdc20, and Kntc2, were less down regulated by JW‐1521 than SAHA. In contrast p53 activated pro‐apoptotic genes such as p21B and Gdf15, were dramatically up regulated by JW‐1521 and only modestly induced by SAHA. These differential levels of gene induction provide molecular evidence of both cell cycle arrest and apoptosis, and suggest that the differential p53 mediated activation of these genes explains the difference in the biological effect of JW‐1521 and SAHA. (Supported by the Coleman Foundation and the Pat Girondi Fellowship in Molecular Medicine)