TP53 Genomic Status Regulates Sensitivity of Gastric Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A (DZNep)

DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unkno...

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Published in:Clinical cancer research 2012-08, Vol.18 (15), p.4201-4212
Main Authors: LAI LING CHENG, ITAHANA, Yoko, MATHIJS VOORHOEVE, Pieter, QIANG YU, PUAY HOON TAN, BOON HUAT BAY, ITAHANA, Koji, TAN, Patrick, ZHENG DENG LEI, CHIA, Na-Yu, YONGHUI WU, YINGNAN YU, SHEN LI ZHANG, THIKE, Aye Aye, PANDEY, Anuradha, ROZEN, Steve
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - pharmacology
Adult
Aged
Aged, 80 and over
Antineoplastic agents
Apoptosis - drug effects
Apoptosis - genetics
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cell Survival - genetics
Enhancer of Zeste Homolog 2 Protein
Female
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic - drug effects
Histones - metabolism
Humans
Immunoblotting
Male
Medical sciences
Methylation - drug effects
Middle Aged
Mutation
Pharmacology. Drug treatments
Polycomb Repressive Complex 2 - genetics
Polycomb Repressive Complex 2 - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Signal Transduction - drug effects
Signal Transduction - genetics
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
Ubiquitination - drug effects
Young Adult
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Summary:DZNep (3-deazaneplanocin A) depletes EZH2, a critical component of polycomb repressive complex 2 (PRC2), which is frequently deregulated in cancer. Despite exhibiting promising anticancer activity, the specific genetic determinants underlying DZNep responsiveness in cancer cells remain largely unknown. We sought to determine molecular factors influencing DZNep response in gastric cancer. Phenotypic effects of DZNep were evaluated in a panel of gastric cancer cell lines. Sensitive lines were molecularly interrogated to identify potential predictors of DZNep responsiveness. The functional importance of candidate predictors was evaluated using short hairpin RNA (shRNA) and siRNA technologies. DZNep depleted PRC2 pathway components in almost all gastric cancer lines, however, only a subset of lines exhibited growth inhibition upon treatment. TP53 genomic status was significantly associated with DZNep cellular responsiveness, with TP53 wild-type (WT) lines being more sensitive (P < 0.001). In TP53-WT lines, DZNep stabilized p53 by reducing ubiquitin conjugation through USP10 upregulation, resulting in activation of canonical p53 target genes. TP53 knockdown in TP53-WT lines attenuated DZNep sensitivity and p53 target activation, showing the functional importance of an intact p53 pathway in regulating DZNep cellular sensitivity. In primary human gastric cancers, EZH2 expression was negatively correlated with p53 pathway activation, suggesting that higher levels of EZH2 may repress p53 activity. Our results highlight an important role for TP53 genomic status in influencing DZNep response in gastric cancer. Clinical trials evaluating EZH2-targeting agents such as DZNep should consider stratifying patients with gastric cancer by their TP53 genomic status.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-12-0036