Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma.
Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma.
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DOI：
10.1186/s13046-022-02506-y
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发表时间：
2022-10-22
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髓母细胞瘤是儿童最常见的恶性脑肿瘤，3组髓母细胞瘤（G3-MB）预后最差。超级增强子（Super enhancer, SEs）是一大类增强子，它们通过转录控制细胞识别基因、癌基因和肿瘤依赖基因在癌症中发挥重要作用。剖析se驱动的癌症转录依赖性有助于鉴定新的致癌机制、治疗策略和靶点。对G3-MB原代组织和患者源性肿瘤细胞系进行综合SE分析，提取保守的SE相关基因特征，并通过基因表达、肿瘤依赖和患者预后分析评估其致癌潜力。se相关亚型特异性上调的肿瘤依赖基因被发现是G3-MB se驱动核心转录调控网络的成员，然后进行功能验证和机制研究。通过基因或药物单独或联合靶向SE复合物组分或SE相关亚型特异性上调的肿瘤依赖基因，进一步探索SE相关的治疗潜力，并研究其潜在的治疗机制。鉴定出的G3-MB组织和细胞系的保守se相关转录本富集了亚型特异性上调的肿瘤依赖基因，并且这些转录本富集的MB患者预后较差。14个这样的保守的se相关的G3-MB特异性上调肿瘤依赖基因被鉴定为se驱动的G3-MB核心转录调控网络的成员，包括3个公认的tf （MYC， OTX2和CRX）和11个新发现的下游效应基因（ARL4D, AUTS2， BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5， SDK2和SSBP3）。进一步发现OTX2-SE-ARL4D调节轴代表G3-MB的亚型特异性肿瘤依赖性和治疗靶点，有助于维持细胞周期进展和抑制肿瘤细胞的神经分化。此外，BET抑制CDK7或蛋白酶体抑制，两种针对SE复合物组分（BRD4, CDK7）或SE相关效应基因（PSMB5）的组合策略，分别通过更强的SE相关转录抑制或更高的内质网应激诱导，显示出对G3-MB的协同治疗效果。我们的研究验证了se驱动的G3-MB转录依赖性的致瘤作用和治疗潜力，从而更好地了解其肿瘤生物学并确定新的se相关治疗策略和靶点。在线版本包含补充材料，可在10.1186/s13046-022-02506-y获得。
Medulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets. Integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined. The identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively. Our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets. The online version contains supplementary material available at 10.1186/s13046-022-02506-y.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
9
作者：
Frisira, Eleni;Rashid, Fatima;Niklison-Chirou, Maria Victoria
通讯作者：
Niklison-Chirou, Maria Victoria
DOI：
10.1158/1078-0432.ccr-13-2281
发表时间：
2014-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bandopadhayay P;Bergthold G;Nguyen B;Schubert S;Gholamin S;Tang Y;Bolin S;Schumacher SE;Zeid R;Masoud S;Yu F;Vue N;Gibson WJ;Paolella BR;Mitra SS;Cheshier SH;Qi J;Liu KW;Wechsler-Reya R;Weiss WA;Swartling FJ;Kieran MW;Bradner JE;Beroukhim R;Cho YJ
通讯作者：
Cho YJ
影响因子：
16.6
作者：
Decaesteker B;Denecker G;Van Neste C;Dolman EM;Van Loocke W;Gartlgruber M;Nunes C;De Vloed F;Depuydt P;Verboom K;Rombaut D;Loontiens S;De Wyn J;Kholosy WM;Koopmans B;Essing AHW;Herrmann C;Dreidax D;Durinck K;Deforce D;Van Nieuwerburgh F;Henssen A;Versteeg R;Boeva V;Schleiermacher G;van Nes J;Mestdagh P;Vanhauwaert S;Schulte JH;Westermann F;Molenaar JJ;De Preter K;Speleman F
通讯作者：
Speleman F