Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.
Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.
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DOI：
10.1016/j.celrep.2020.108293
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发表时间：
2020-10-20
期刊：
影响因子：
8.8
通讯作者：
Rai K
中科院分区：
文献类型：
--
作者：
Maitituoheti M;Keung EZ;Tang M;Yan L;Alam H;Han G;Singh AK;Raman AT;Terranova C;Sarkar S;Orouji E;Amin SB;Sharma S;Williams M;Samant NS;Dhamdhere M;Zheng N;Shah T;Shah A;Axelrad JB;Anvar NE;Lin YH;Jiang S;Chang EQ;Ingram DR;Wang WL;Lazar A;Lee MG;Muller F;Wang L;Ying H;Rai K
组蛋白甲基转移酶 KMT2D 在多种肿瘤类型（包括黑色素瘤）中经常出现功能丧失的体细胞点突变。在这里，我们通过体内表观基因组集中 RNAi 筛选确定 KMT2D 是黑色素瘤中的有效肿瘤抑制因子，并通过使用基于条件性和黑素细胞特异性删除 KMT2D 的基因工程小鼠模型 (GEMM) 证实了这一发现。 KMT2D 缺陷的肿瘤表现出关键代谢途径的实质性重编程，包括糖酵解。 KMT2D 缺陷会异常上调糖酵解酶、中间代谢产物和葡萄糖消耗率。从机制上讲，KMT2D 缺失会导致全基因组范围内 H3K4me1 标记的活性增强子染色质状态减少。增强子丢失和随后 IGFBP5 的抑制会激活 IGF1R-AKT，从而增加 KMT2D 缺陷细胞中的糖酵解。糖酵解和胰岛素生长因子 (IGF) 信号传导的药理学抑制优先减少 KMT2D 缺陷细胞的增殖和肿瘤发生。我们得出的结论是，KMT2D 缺失通过增强子重编程促进糖酵解途径的增加使用来增加生物量需求，从而促进肿瘤发生，从而为通过糖酵解或 IGF 途径抑制剂进行治疗干预提供了机会。通过体内表观基因组集中 RNAi 筛选，Maitituoheti 等人。确定 KMT2D 是黑色素瘤的肿瘤抑制因子。 KMT2D 缺陷型肿瘤通过减少 H3K4me1 标记的活性增强子，表现出关键代谢途径的实质性重编程，从而赋予具有 KMT2D 失活突变的黑色素瘤对糖酵解和 IGFR 抑制剂的敏感性。
Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors. Through an in vivo epigenome-focused pooled RNAi screen, Maitituoheti et al. identify KMT2D as a tumor suppressor in melanoma. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways by reduction of H3K4me1-marked active enhancers, conferring sensitivity to glycolysis and IGFR inhibitors in melanoma with KMT2D-inactivating mutations.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
30.8
作者：
da Silva Almeida AC;Abate F;Khiabanian H;Martinez-Escala E;Guitart J;Tensen CP;Vermeer MH;Rabadan R;Ferrando A;Palomero T
通讯作者：
Palomero T
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
14.8
作者：
Garcia, Benjamin A.;Mollah, Sahana;Hunt, Donald F.
通讯作者：
Hunt, Donald F.