The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53

Cancer Biol Ther. 2002 Nov-Dec;1(6):665-8. doi: 10.4161/cbt.317.

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.

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • DNA Damage / drug effects
  • DNA Primers / chemistry
  • Depsipeptides*
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors*
  • Humans
  • Nuclear Proteins*
  • Peptides, Cyclic / pharmacology*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Transcriptional Activation
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA Primers
  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Nuclear Proteins
  • Peptides, Cyclic
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • romidepsin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2