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

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 BardeesyTodd W. Bauer, Mazhar Adli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1331-1346.e9
JournalDevelopmental Cell
Volume57
Issue number11
DOIs
StatePublished - Jun 6 2022

Keywords

  • CRISPR
  • ISL2
  • pancreatic cancer
  • tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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