ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer

• Published in: Developmental cell Vol. 57; no. 11; pp. 1331 - 1346.e9
• Main Authors: Ozturk, Harun, Cingoz, Harun, Tufan, Turan, Yang, Jiekun, Adair, Sara J., Tummala, Krishna Seshu, Kuscu, Cem, Kinali, Meric, Comertpay, Gamze, Nagdas, Sarbajeet, Goudreau, Bernadette J., Luleyap, Husnu Umit, Bingul, Yagmur, Ware, Timothy B., Hwang, William L., Hsu, Ku-lung, Kashatus, David F., Ting, David T., Chandel, Navdeep S., Bardeesy, Nabeel, Bauer, Todd W., Adli, Mazhar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2022
• Subjects: Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; CRISPR; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor; Humans; ISL2; LIM-Homeodomain Proteins - genetics; LIM-Homeodomain Proteins - metabolism; Nerve Tissue Proteins - metabolism; pancreatic cancer; Pancreatic Neoplasms - metabolism; Transcription Factors - metabolism; Tumor Microenvironment - genetics; tumor suppressor; CRISPR; tumor suppressor; ISL2; pancreatic cancer
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.04.014

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. [Display omitted] •In vivo CRISPR screening identified ISL2 as a tumor suppressor•ISL2 is epigenetically silenced in a large fraction of pancreatic tumors•ISL2 downregulation reprograms the metabolism of pancreatic cancer cells•ISL2 inactivation can be exploitable therapeutically Ozturk et al. identify ISL2 as a tumor suppressor of pancreatic cancer growth. They find that ISL2 is epigenetically silenced in a significant fraction of pancreatic tumors, and reduced ISL2 expression reprograms metabolic genes in cancer cells to rely on mitochondrial metabolism rather than glycolysis.