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The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53
Masaki Kitazono1, Susan Bates, Patrick Fok
1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Abstract:
We have previously described a novel mechanism of p53 dysfunction, characterized by repression of mRNA and protein expression effectively leading to functional inactivation of wt p53 in SW-1736 human anaplastic thyroid cancer cells (pseudo-null p53). Here we demonstrated that treatment of SW-1736 cells with sub-cytotoxic concentrations of FR901228, a histone deacetylase (HDAC) inhibitor, results in marked induction of p53 mRNA and protein. The p53 induced by FR901228 was functional as evidenced by mdm-2 and p21 transactivation, and its further accumulation following DNA damage by doxorubicin. Furthermore, pretreatment with FR901228 sensitized SW-1736 cells to doxorubicin. This study validates the concept of pseudo-null p53, as a mechanism of p53 inactivation, and demonstrates that pseudo-null p53 can be rescued pharmacologically.
Insights
Histone deacetylase (HDAC) inhibitor FR901228 rescues functional wild-type p53 in anaplastic thyroid cancer cells with pseudo-null p53. This approach restores p53 activity and sensitizes cells to chemotherapy, validating a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Anaplastic thyroid cancer (ATC) cells can exhibit functional inactivation of wild-type p53 (wt p53) via mRNA and protein expression repression, termed pseudo-null p53.
- Understanding mechanisms of p53 inactivation is crucial for developing targeted therapies in ATC.
Purpose of the Study:
- To investigate the effect of histone deacetylase (HDAC) inhibitor FR901228 on pseudo-null p53 in SW-1736 ATC cells.
- To determine if pharmacologic intervention can restore functional p53 activity in this context.
Main Methods:
- Treatment of SW-1736 cells with sub-cytotoxic concentrations of FR901228.
- Assessment of p53 mRNA and protein levels.
- Evaluation of p53 functionality through mdm-2 and p21 transactivation assays.
- Analysis of p53 accumulation after doxorubicin-induced DNA damage.
- Assessment of cell sensitization to doxorubicin following FR901228 pretreatment.
Main Results:
- FR901228 treatment significantly induced p53 mRNA and protein expression in SW-1736 cells.
- The induced p53 demonstrated functionality, evidenced by successful transactivation of mdm-2 and p21.
- FR901228-induced p53 further accumulated upon doxorubicin treatment, indicating restored DNA damage response.
- Pretreatment with FR901228 sensitized SW-1736 cells to doxorubicin, enhancing chemotherapy efficacy.
Conclusions:
- The study validates pseudo-null p53 as a mechanism of p53 inactivation in ATC.
- Pharmacological rescue of pseudo-null p53 is achievable using HDAC inhibitors like FR901228.
- Targeting p53 restoration presents a viable therapeutic strategy for anaplastic thyroid cancer.