機能の獲得p53変異体は,がんの成長を誘導するクロマチンの経路を共用する

Jiajun Zhu^1,2,3, Morgan A Sammons^1,2, Greg Donahue^1,2

¹Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Nature

|September 3, 2015

まとめ

MLL1のようなクロマチンの変形剤を上調することで,TP53の機能獲得変異は癌を促進する. これらの変形剤を阻害すると,がん細胞の増殖が減り,TP53変異がんの新たな治療標的が明らかになる.

科学分野:

腫瘍学
エピジェネティクス
分子生物学

背景:

TP53はヒトがんで最も頻繁に変異した遺伝子です.
ゲイン・オブ・ファンクション (GOF) p53変異は,遺伝子発現を変化させることで腫瘍形成を促進する.
GOF p53ががんの進行を促す正確なメカニズムは完全に理解されていません.

研究の目的:

染色体改変酵素の調節におけるp53 GOF変異の役割を調査する.
p53 GOF変異を有するがんの新たな治療標的を特定する.

主な方法:

ガンゲノムアトラス (TCGA) のデータ分析
染色体調節遺伝子 (MLL1,MLL2,MOZ) の遺伝子発現分析
MLL1の遺伝的ノックダウンと薬理学的阻害を含む機能研究

主要な成果:

p53GOF変異体は,クロマチンの調節遺伝子MLL1,MLL2およびMOZを上位に調節する.
MLL1,MLL2およびMOZは,野生型またはゼロ型腫瘍と比較して,p53GOF腫瘍において特異的に上位調節されている.
MLL1のノックダウンまたはメチルトランスフェラーゼ複合体の抑制は,癌細胞の増殖を著しく減少させます.

結論:

p53 GOF変異は,MLL1,MLL2,MOZを含む新しい染色体ベースのメカニズムを通じてがんの進行を促します.
GOF p53変異を持つがんの治療には,これらのクロマチンの変形剤をターゲットにすることが有望な治療戦略です.

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