| First Author | Ozturk H | Year | 2022 |
| Journal | Dev Cell | Volume | 57 |
| Issue | 11 | Pages | 1331-1346.e9 |
| PubMed ID | 35508175 | Mgi Jnum | J:351204 |
| Mgi Id | MGI:7286405 | Doi | 10.1016/j.devcel.2022.04.014 |
| Citation | Ozturk H, et al. (2022) ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer. Dev Cell 57(11):1331-1346.e9 |
| abstractText | 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. |
