KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1

// Mei-Ting Qiu 1, * , Qiong Fan 1, * , Zhu Zhu 2, * , Suet-Ying Kwan 2 , Limo Chen 3 , Jin-Hong Chen 4 , Zuo-Lin Ying 5 , Ye Zhou 1 , Wei Gu 1 , Li-Hua Wang 1 , Wei-Wei Cheng 1 , Jianfang Zeng 6 , Xiao-Ping Wan 4 , Samuel C. Mok 2 , Kwong-Kwok Wong 2 , Wei Bao 1, 2 1 Departments of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, Shanghai, China 2 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Departments of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, TongJi University School of Medicine, Shanghai, China 5 Department of Dermatology, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China 6 Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Wei Bao, e-mail: forever_chipper@hotmail.com Keywords: endometrial cancer, lysine demethylases KDM4B and KDM4A, androgen receptor, histone modification, c-myc, p27 kip1 , prognosis Received: May 21, 2015      Accepted: August 29, 2015      Published: September 11, 2015 ABSTRACT 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.