Journal
ONCOTARGET
Volume 6, Issue 31, Pages 31702-31720Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5165
Keywords
endometrial cancer; lysine demethylases KDM4B and KDM4A; androgen receptor; histone modification; c-myc; p27(kip1); prognosis
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Funding
- National Natural Science Foundation of China [81402134]
- Science and Technology Commission of Shanghai Municipality [12ZR1451400]
- Young Scientific Research Project of Shanghai Municipal Health Bureau [20124Y045]
- Scientific Project Chen-Xing Plan of Shanghai Jiao Tong University
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Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27(kip1). Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity.
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