Disruption of the MSL complex inhibits tumour maintenance by exacerbating chromosomal instability.
Disruption of the MSL complex inhibits tumour maintenance by exacerbating chromosomal instability.
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DOI：
10.1038/s41556-021-00657-2
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发表时间：
2021-04
影响因子：
21.3
通讯作者：
Scaffidi P
中科院分区：
文献类型：
--
作者：
Monserrat J;Morales Torres C;Richardson L;Wilson TS;Patel H;Domart MC;Horswell S;Song OR;Jiang M;Crawford M;Bui M;Dalal Y;Scaffidi P
恶性细胞中细胞程序的重新布线产生癌症特异性脆弱性。在这里，使用无偏筛选策略，旨在确定肿瘤细胞维持无限增殖能力所需的非必需基因，我们确定了男性特异性致死（MSL）乙酰转移酶复合物作为遗传不稳定癌症的脆弱性。我们发现，MSL复合物的破坏和随之而来的相关H4K16ac标记的丢失不会显著改变转录程序，但会损害染色体完整性并促进染色体不稳定性（CIN），从而通过p53非依赖性机制逐渐耗尽癌细胞的增殖潜力。这种效应依赖于预先存在的基因组不稳定性，正常细胞对MSL破坏不敏感。使用来自多种癌症类型的细胞和患者来源的异种移植物，我们表明由MSL破坏诱导的过度CIN抑制肿瘤维持。我们的研究结果表明，靶向MSL可能是一种有价值的手段，增加CIN超过癌细胞耐受的水平，而不会在正常组织中诱导严重的不良反应。
Rewiring of cellular programs in malignant cells generates cancer-specific vulnerabilities. Here, using an unbiased screening strategy aimed at identifying non-essential genes required by tumor cells to sustain unlimited proliferative capacity, we identify the Male-Specific Lethal (MSL) acetyltransferase complex as a vulnerability of genetically unstable cancers. We find that disruption of the MSL complex and consequent loss of the associated H4K16ac mark do not substantially alter transcriptional programs, but compromise chromosome integrity and promote chromosomal instability (CIN) that progressively exhausts the proliferative potential of cancer cells through a p53-independent mechanism. This effect is dependent on pre-existing genomic instability and normal cells are insensitive to MSL disruption. Using cell- and patient-derived xenografts from multiple cancer types, we show that excessive CIN induced by MSL disruption inhibits tumor maintenance. Our findings suggest that targeting of MSL may be a valuable means to increase CIN beyond the level tolerated by cancer cells without inducing severe adverse effects in normal tissues.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
64.8
作者：
Baell, Jonathan B.;Leaver, David J.;Thomas, Tim
通讯作者：
Thomas, Tim
影响因子：
64.8
作者：
Lan X;Jörg DJ;Cavalli FMG;Richards LM;Nguyen LV;Vanner RJ;Guilhamon P;Lee L;Kushida MM;Pellacani D;Park NI;Coutinho FJ;Whetstone H;Selvadurai HJ;Che C;Luu B;Carles A;Moksa M;Rastegar N;Head R;Dolma S;Prinos P;Cusimano MD;Das S;Bernstein M;Arrowsmith CH;Mungall AJ;Moore RA;Ma Y;Gallo M;Lupien M;Pugh TJ;Taylor MD;Hirst M;Eaves CJ;Simons BD;Dirks PB
通讯作者：
Dirks PB
影响因子：
64.8
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
通讯作者：
Murray SA
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B