LSD1 binds to HPV16 E7 and promotes the epithelial-mesenchymal transition in cervical cancer by demethylating histones at the Vimentin promoter

// Yuan Liu 1, * , Yanan Wang 1, * , Chunqin Chen 1, * , Jiawen Zhang 1, 2 , Wenyan Qian 3 , Yu Dong 4 , Zhiqiang Liu 5 , Xi Zhang 6 , Xiaoyun Wang 1 , Zhenbo Zhang 1 , Xiaobing Shi 7, 8 , Sufang Wu 1 1 Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China 2 Department of Obstetrics and Gynecology, Shanghai Tenth People’s Hospital, Shanghai Tongji University, Shanghai, China 3 Department of Gynecology and Obstetrics, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China 4 Department of Obstetrics and Gynecology, Shanghai Xinhua hospital, Shanghai Jiaotong University, Shanghai, China 5 Division of Cancer Medicine, Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 6 Department of Physiology and Neurobiology, University of Connecticut, CT, USA 7 Department of Molecular Carcinogenesis and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Genes and Development and Molecular Carcinogenesis Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Sufang Wu, email: wsf_sfph@sjtu.edu.cn Keywords: LSD1, HPV16E7, cervical cancer, EMT Received: May 11, 2016 Accepted: October 17, 2016 Published: November 23, 2016 ABSTRACT Lysine-specific demethylase 1 (LSD1), which specifically demethylates histone H3 lysine 4 (H3K4) and lysine 9 (H3K9), is dysregulated in several cancers. We found that ectopic expression of LSD1 in cervical cancer cells promoted invasion and metastasis in vitro and in vivo , reduced the expression of the epithelial marker E-cadherin, and induced the expression of the mesenchymal marker, Vimentin. By contrast, LSD1 knockdown had the opposite effect and attenuated the HPV16 E7-induced epithelial-mesenchymal transition (EMT). We proposed a novel mechanism, whereby LSD1 is recruited to the Vimentin promoter and demethylates H3K4me1 and H3K4me2. Notably, HPV16 E7 enhanced the expression of LSD1, formed a complex with LSD1, and suppressed LSD1 demethylase activity by hindering the recruitment of LSD1 to the Vimentin promoter. Thus, LSD1 is a primary and positive regulator of the HPV16 E7-induced EMT and an attractive therapeutic target for alleviating HPV16 E7-induced EMT and tumor metastasis.