α-ケトグルタレットは,腫瘍抑制中のp53と細胞運命を結びつける

John P Morris¹, Jossie J Yashinskie^2,3,4, Richard Koche³

¹Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Nature

|September 20, 2019

まとめ

アルファケトグルタレート (αKG) を増加させ,分化を促進し,腫瘍の成長を抑制します. 臓がんにおけるp53機能の回復は悪性進行を止めます.

科学分野:

癌生物学
代謝の調節
エピジェネティクス

背景:

TP53腫瘍抑制遺伝子は,臓管内腺がん (PDAC) を含むヒトがんで頻繁に変異する.
ワイルド型p53は遺伝子発現と細胞代謝を調節するが,代謝変化による癌の進行を抑制する役割は不明である.
p53の代謝の影響を理解することは,標的型がん治療の開発に不可欠です.

研究の目的:

染色体と遺伝子発現に影響を与えるために,p53が癌細胞の代謝をどのように再構成するかを調査する.
アルファケトグルタレート (αKG) がp53の腫瘍抑制機能の媒介者としての役割を明らかにする.
p53欠乏がんにおける代謝経路を標的とした治療戦略を探求する.

主な方法:

PDACのKRAS変異マウスモデルを使用して,p53機能の回復を研究した.
αKGを含む量化された代謝物レベルと,5-ヒドロキシメチルサイトシン (5hmC) のようなクロマチンの改変を評価した.
代謝酵素活性 (例えば,オックスグルタレット脱水素酶抑制) を操作する遺伝的および薬理学的アプローチが採用された.

主要な成果:

PDAC細胞におけるp53機能の回復はαKGの蓄積につながり,分化関連転写プログラムを引き起こした.
癌前分化に関連したクロマチンのマークである5hmCの上昇と相関するαKG濃度の上昇.
p53欠乏細胞におけるオックスグルタレット脱水素酵素の抑制は,αKGを増加させ,分化を促進し,腫瘍細胞の適性を低下させた.

結論:

αKGは,クロマチンの状態と細胞運命を影響することによって,p53媒介の腫瘍抑制の重要なエフェクタとして作用する.
αKGの蓄積は,p53欠乏症のPDACの分化および悪性進行を阻害する.
αKGの代謝をターゲットにすることは,p53変異した癌の潜在的な治療戦略です.

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