FBXO44は,がん細胞におけるDNA複製結合の繰り返し要素の静止を促進する

Jia Z Shen¹, Zhixin Qiu², Qiulian Wu²

¹Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Cell

|December 28, 2020

まとめ

FBXO44とSUV39H1は通常ゲノム内の反復要素を静止しますがん細胞でそれらを阻害すると,これらの元素が再活性化され,複製のストレスが発生し,抗腫瘍免疫が強化されます.

科学分野:

ゲノミクス
エピジェネティクス
癌生物学

背景:

ヒトゲノムの約50%を構成している.
REsのトランスクリプションサイレンスに関する正確なメカニズムは,ほとんど不明である.
REsの調節不良は,がんを含む様々な病理に関与しています.

研究の目的:

繰り返す要素 (RE) の転写の新しいレギュレータを特定する.
REサイレンスにおけるFBXO44の役割とそのがんへの影響について解明する.
RE抑制経路を標的とした治療の可能性を調査する.

主な方法:

RE抑制剤を特定するためのRNA干渉 (RNAi) スクリーニング
タンパク質と核細胞の相互作用を研究するためのクロマチン免疫降水 (ChIP) 測定法.
DNA複製ストレスマーカーと抗ウイルス信号経路 (MAVS/STING) の分析
FBXO44発現とヒトがんにおける免疫細胞浸透の相関研究

主要な成果:

FBXO44は,がん細胞におけるREsの主要な抑制剤として特定されました.
FBXO44はSUV39H1とCRL4とMi-2/NuRDを駆使して複製後のREsを沈黙させる.
FBXO44/SUV39H1が再活性化され,複製ストレスが誘発され,MAVS/STING/インターフェロン経路が活性化されます.
FBXO44/SUV39H1の阻害は,がん細胞に選択的に影響を及ぼし,正常な細胞には影響を及ぼさなかった.
FBXO44の発現は免疫マーカーと逆相関し,患者の免疫療法反応と正相関した.

結論:

FBXO44とSUV39H1は,がんにおけるREsの転写性静止を維持するために重要である.
FBXO44/SUV39H1をターゲットにすると,選択的にがん細胞におけるDNA複製ストレスとウイルスのミミクリが誘発されます.
この戦略は,がんの免疫原性を高め,免疫療法への反応を改善します.

キーワード:

FBXO44 H3K9me3 について SUV39H1 免疫療法繰り返される要素

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