2021 Fiscal Year Final Research Report
Novel cancer therapeutic strategy focusing on drug resistance via epigenetic regulation on endoplasmic reticulum stress response
| Project/Area Number |
20K17349
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Keywords | メラノーマ / SWI/SNF複合体 / ARID2 / がん化進展 / 腫瘍免疫 / HDAC / NOTCHシグナル / NUMB |
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| Outline of Final Research Achievements |
AT-rich interactive domain-containing protein 2 (ARID2), a subunit of SWI/SNF complex, regulates chromatin remodeling and is highly mutated in melanoma. The implication of ARID2 mutation on melanomagenesis has not been known well. In this study, we elucidated the regulation of ARID2 on the proliferative and invasive potential of melanoma. Furthermore, as many subunits of SWI/SNF complex have been reported to modulate cancer immunity, we showed in this study that ARID2 affects the response of melanoma cells to immune checkpoint inhibitors.
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| Free Research Field |
色素細胞
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| Academic Significance and Societal Importance of the Research Achievements |
当初の目的の１つであったエピジェネティクス治療薬のHDAC阻害剤のメラノーマにおける治療戦略の確立には至らなかった。しかし、新規治療戦略の探索という点では、NOTCHシグナルの抑制機能で知られるNUMB が、メラノーマにおいても他の癌種同様に、癌抑制因子として機能することを解明した。さらに、NUMBのloss of functionが、cyclin E の発現上昇を介して、メラノーマ浸潤能の増加に繋がることを証明した。最後に、グリコーゲン合成酵素キナーゼ-3阻害剤がNUMB依存的にメラノーマ細胞の浸潤を減少させ、新規の治療標的となり得る可能性を提示できた点は本研究の社会的意義と考える。
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