The role of BMP signaling in bone metastasis by malignant melanoma

• Project/Area Number: 17K17284
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: Shigeyama Yukiyo 九州歯科大学, 歯学部, 助教 (10794480)
• Research Collaborator: OGAWA masahiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 悪性黒色腫 / BMP / TLE3 / HDAC / BMPシグナル / EMT / 癌 / シグナル伝達

Outline of Final Research Achievements

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. Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation 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. In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation. Treatment of B16 cells with trichostatin A, a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation.

Academic Significance and Societal Importance of the Research Achievements

近年、抗PD-1抗体nivolumabなどの免疫チェックポイント阻害剤の登場により悪性黒色腫の治療成績が著しく向上してきたが、これら薬剤は間質性肺炎や大腸炎など様々な臓器に対して免疫関連有害事象をもたらすことも明らかとなってきた。そのため、悪性黒色腫の病態を正確に理解し、新たな治療法を確立する必要性は依然として残っている。ヒストン脱アセチル化酵素（HDAC）阻害剤は悪性黒色腫の新規治療薬として注目されている。本研究はTLE3の悪性黒色腫細胞の増殖促進作用にHDACが関与することを明らかにしたものであり、HDAC阻害剤を利用した悪性黒色腫の治療法に新たなエビデンスを提唱することができたと考える。

Research Products

• [Int'l Joint Research] McGill University(カナダ)
• [Journal Article] Transducin-like Enhancer of Split 3 regulates proliferation of melanoma cells via histone deacetylase activity. (2019)
  • Author(s): Ogawa M, Yaginuma T, Nakatomi C, Nakajima T, Tada-Shigeyama Y, Addison WN, Urata M, Matsubara M, Watanabe K, Matsuo K, Sato T, Honda H, Hikiji H, Watanabe S, Kokabu S
  • Journal Title: Oncotarget Volume: 10(3) Issue: 21 Pages: 404-414
  • DOI: 10.18632/oncotarget.2655
  • Peer Reviewed / Open Access / Int'l Joint Research