Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity

// Masahiro Ogawa 1, 2 , Tatsuki Yaginuma 1 , Chihiro Nakatomi 1 , Tsuyoshi Nakajima 1 , Yukiyo Tada-Shigeyama 2 , William N. Addison 3 , Mariko Urata 1 , Takuma Matsubara 1 , Koji Watanabe 4 , Kou Matsuo 5 , Tsuyoshi Sato 6 , Hiromi Honda 7 , Hisako Hikiji 7 , Seiji Watanabe 2 and Shoichiro Kokabu 1 1 Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan 2 Division of Dental Anesthesiology, Department of Science of Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan 3 Research Unit, Shriners Hospitals for Children-Canada, Department of Human Genetics, McGill University, Montreal, Quebec, Canada 4 Division of Developmental Stomatognathic Function Science, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan 5 Division of Oral Pathology, Department of Health Improvement, Kyushu Dental University, Kitakyushu, Fukuoka, Japan 6 Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan 7 School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Fukuoka, Japan Correspondence to: Shoichiro Kokabu, email: r14kokabu@fa.kyu-dent.ac.jp Keywords: malignant melanoma; transcriptional co-repressor; trichostatin A; HDAC inhibitors Received: August 12, 2018     Accepted: December 20, 2018     Published: January 08, 2019 ABSTRACT Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 μM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.