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ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer
- Source :
- Developmental cell. 57(11)
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- LIM-Homeodomain Proteins
Nerve Tissue Proteins
Cell Biology
General Biochemistry, Genetics and Molecular Biology
Epigenesis, Genetic
Pancreatic Neoplasms
Cell Line, Tumor
Tumor Microenvironment
Humans
Genes, Tumor Suppressor
Molecular Biology
Developmental Biology
Carcinoma, Pancreatic Ductal
Transcription Factors
Subjects
Details
- ISSN :
- 18781551
- Volume :
- 57
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Developmental cell
- Accession number :
- edsair.doi.dedup.....0f2e0e642572c6c4aa1439895ffe9fc4