PRIMA-1, a mutant p53 reactivator, restores the sensitivity of TP53 mutant-type thyroid cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A.

Abstract

CONTEXT:

3-Deazaneplanocin A (DZNep) depletes enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2 (PRC2), which is frequently overexpressed in human cancers. DZNep exhibits promising antitumor activity, and its responsiveness in cancer cells is determined by certain genetic factors.

OBJECTIVES:

Our aims were (1) to test the therapeutic potential of DZNep and explore the genetic determinants affecting the DZNep response in thyroid cancer cells and (2) to test the combined therapeutic effect of DZNep and PRIMA-1, a mutant p53 reactivator, in thyroid cancer.

EXPERIMENTAL DESIGN:

We evaluated the phenotypic effects of DZNep in thyroid cancer cells and examined the effects of DZNep alone or in combination with PRIMA-1 on cell proliferation, the cell cycle, apoptosis, and xenograft tumor growth.

RESULTS:

DZNep induced enhancer of zeste homolog 2 depletion and trimethylated lysine 27 in H3 histone (H3K27me3) mark reduction in all thyroid cancer cells; however, only TP53 wild-type cells exhibited growth inhibition with DZNep treatment. In these cells, DZNep caused p53 protein accumulation through up-regulation of USP10 expression, resulting in activation of the p53 pathway, contributing to inhibition of cell growth. Conversely, TP53 mutant-type cells were resistant to DZNep. Strikingly, the combination of DZNep with PRIMA-1 restored the sensitivity of TP53 mutant-type cells to DZNep. A similar antitumor effect of DZNep and PRIMA-1 alone or in combination was also seen in xenograft tumor models.

CONCLUSION:

Our data demonstrated that DZNep responsiveness was strongly associated with TP53 genomic status in thyroid cancer cells. Reactivation of p53 restored the sensitivity of TP53 mutant-type cells to DZNep. Thus, a combined therapeutic strategy may be effective in treating thyroid cancer cells (or patients) harboring mutant p53.

• Authors: Bo Cui, Qi Yang, Haixia Guan, Bingyin Shi, Peng Hou, Meiju Ji
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 99 Issue 6 Pg. E962-70 (Jun 2014) ISSN: 1945-7197 [Electronic] United States
• PMID: 24512488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Mutant Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• 3-deazaneplanocin
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
• Adenosine

Topics

• Adenosine (administration & dosage, analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Aza Compounds (administration & dosage, pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, pharmacology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Humans
• Mice
• Mice, Nude
• Mutant Proteins (drug effects)
• Thyroid Neoplasms (drug therapy, pathology)
• Tumor Suppressor Protein p53 (drug effects, genetics)
• Xenograft Model Antitumor Assays