Epigenetic silencing of HOPX is critically involved in aggressive phenotypes and patient prognosis in papillary thyroid cancer

// Yosuke Ooizumi 1 , * , Hiroshi Katoh 2 , * , Mitsuo Yokota 1 , 2 , Masahiko Watanabe 1 and Keishi Yamashita 1 , 3 1 Department of Surgery, Kitasato University Hospital, Kanagawa, Japan 2 Breast and Endocrine Surgery, Kitasato University Hospital, Kanagawa, Japan 3 Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University Hospital, Kanagawa, Japan * These authors contributed equally to this work Correspondence to: Keishi Yamashita, email: keishi23@med.kitasato-u.ac.jp Keywords: HOPX; papillary thyroid cancer; epigenetic silencing; promoter methylation Received: November 22, 2018     Accepted: August 12, 2019     Published: October 15, 2019 ABSTRACT HOPX is involved in multiple organ development and acts as a tumor suppressor in various cancers. Epigenetic silencing of HOPX via its promoter methylation has been shown frequent and cancer-specific in human cancers. The proliferation of thyroid cancer cells and cancer progression are strongly influenced by epigenetic alterations as well as genetic changes. Papillary thyroid cancer (PTC) comprises the vast majority of thyroid cancers and exhibits slow progression. However, ~10% of patients still show disease recurrence and refractoriness to treatment. Accordingly, it is important approach to research epigenetic mechanisms in PTC progression to find useful biomarkers. Here, we aimed to seek into the roles and clinical impact of epigenetic silencing of HOPX in PTC. The promoter methylation of HOPX was observed in five of six human thyroid cancer cell lines. Down-regulation of HOPX was seen in three cell lines including PTC line K1, and demethylating agents restored HOPX expression. The promoter methylation was observed with high sensitivity and specificity in human PTC tissues. HOPX promoter methylation independently predicted disease recurrence in PTC patients. Epigenetic silencing of HOPX was associated with Ki-67 expression. Of note, HOPX promoter methylation was dramatically associated with worse prognosis especially in patients with stage I PTC. Forced HOPX expression suppressed cell proliferation, invasive activities, and anchorage-independent growth in vitro . HOPX promoter methylation is frequent and cancer-specific event, leading to aggressive phenotype in PTC. Epigenetic silencing of HOPX may be a clue to tackle cancer progression and have clinical impact as a novel biomarker in PTC.