MYC誘発がん治療のためのSEC障害による漸進的転写延長をターゲットにする

Kaiwei Liang¹, Edwin R Smith², Yuki Aoi¹

¹Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Cell

|October 20, 2018

まとめ

研究者らは,超伸縮複合体 (SEC) を阻害するKL-1とKL-2という化合物を発見しました. この阻害は転写,熱ショック反応,MYC活性に影響し,MYC誘発がんの治療の可能性を示しています.

科学分野:

分子生物学
生物化学
癌研究

背景:

超延伸複合体 (SEC) は,RNAポリメラーゼII (Pol II) の放出と過程性を促進することによって,効率的な遺伝子転写に不可欠である.
SECの機能障害は,がんを含む様々な人間の病気に関与しています.

研究の目的:

SECの機能を妨げる小さな分子を特定する.
癌におけるSEC阻害剤の治療の可能性を調査する.

主な方法:

ペプチドミメティック化合物KL-1とKL-2の特定
KL-1とKL-2がPol IIの放出と転写の伸び率に与える影響を評価する.
種間の熱ショック遺伝子誘導に対するSEC抑制の効果を評価する.
MYCとMYC依存遺伝子のダウンレギュレーションを分析する.
MYC駆動がんのマウス異種移植モデルでの有効性の試験

主要な成果:

KL-1とKL-2は,SEC内のAFF4-P-TEFb相互作用を妨害する化合物として特定されました.
これらの化合物は,パウズサイトからのPol IIの放出を阻害し,転写延長率を低下させます.
KL-1とKL-2によるSEC阻害は,ドロソフィラとヒトの細胞の両方で熱ショック反応を弱める.
SECの抑制は,哺乳類の細胞におけるMYCとその下流転写標的をダウンレギュレーションする.
KL- 1とKL- 2による治療は,MYC誘発がんのマウスモデルで腫瘍の進行を遅らせた.

結論:

KL-1やKL-2のようなSECを標的とする小分子阻害剤は,転写と細胞のストレス反応を効果的に損なうことができます.
SEC阻害は,腫瘍性転写プログラムのダウンレギュレーションによって,MYC駆動がんの治療の可能性を示しています.

キーワード:

MYC について SEC についてプロセッシブな延長プロモーター・プロキシマル・パウシング超伸縮複合体トランスクリプション延長癌における転写依存症

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