Melatonin exerts anti-oral cancer effect via suppressing LSD1 in patient-derived tumor xenograft models

Abstract

// Cheng-Yu Yang 1, 6 , Chih-Kung Lin 3 , Chang-Huei Tsao 7, 8 , Cheng-Chih Hsieh 5 , Gu-Jiun Lin 4 , Kuo-Hsing Ma 4 , Yi-Shing Shieh 6 , Huey-Kang Sytwu 1, 7 and Yuan-Wu Chen 1, 2, 6 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2 Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, Taipei, Taiwan 3 Division of Anatomic Pathology, Taipei Tzu Chi Hospital, Taipei, Taiwan 4 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan 5 Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan 6 School of Dentistry, National Defense Medical Center, Taipei, Taiwan 7 Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan 8 Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan Correspondence to: Yuan-Wu Chen, email: h6183@yahoo.com.tw Keywords: patient-derived tumor xenograft, LSD1, melatonin, oral cancer, cell proliferation Received: June 16, 2016      Accepted: March 08, 2017      Published: April 04, 2017 ABSTRACT Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models. By assessing oral squamous cell carcinoma (OSCC) tissue arrays through immunohistochemistry, we examined whether aberrant LSD1 overexpression in OSCC is associated with poor prognosis. We also evaluated the action mechanism of melatonin against OSCC with lymphatic metastases by using the PDTX models. Our results indicated that melatonin, at pharmacological concentrations, significantly suppresses cell proliferation in a dose- and time-dependent manner. The observed suppression of proliferation was accompanied by the melatonin-mediated inhibition of LSD1 in oral cancer PDTXs and oral cancer cell lines. In conclusion, we determined that the beneficial effects of melatonin in reducing oral cancer cell proliferation are associated with reduced LSD1 expression in vivo and in vitro .