生物
胰腺癌
癌症研究
DNA甲基化
表观遗传学
基因沉默
染色质
下调和上调
转录组
细胞生物学
抑癌基因
抑制器
基因表达调控
转录因子
作者
Harun Ozturk,Harun Cingoz,Turan Tufan,Jiekun Yang,Sara J. Adair,Krishna Seshu Tummala,Cem Kuscu,Meric Kinali,Gamze Comertpay,Sarbajeet Nagdas,Bernadette J. Goudreau,Husnu Umit Luleyap,Yagmur Bingul,Timothy B. Ware,Wiliam L. Hwang,Ku-lung Hsu,David F. Kashatus,David T. Ting,Navdeep S. Chandel,Nabeel Bardeesy,Todd W. Bauer,Mazhar Adli
标识
DOI:10.1016/j.devcel.2022.04.014
摘要
Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.
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