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ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer.
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, Wiliam L; Hsu, Ku-Lung; Kashatus, David F; Ting, David T; Chandel, Navdeep S; Bardeesy, Nabeel; Bauer, Todd W; Adli, Mazhar.
Afiliación
  • Ozturk H; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA.
  • Cingoz H; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA.
  • Tufan T; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Yang J; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Adair SJ; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Tummala KS; Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Kuscu C; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Kinali M; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA.
  • Comertpay G; Cukurova University, Adana 01330, Turkey.
  • Nagdas S; Department of Cell, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Goudreau BJ; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Luleyap HU; Cukurova University, Adana 01330, Turkey.
  • Bingul Y; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA.
  • Ware TB; Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
  • Hwang WL; Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Hsu KL; Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
  • Kashatus DF; Department of Cell, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Ting DT; Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Chandel NS; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Pulmonary and Critical Care and Department of Biochemistry and Molecular Genetics, Chicago, IL 60611, USA.
  • Bardeesy N; Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Bauer TW; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
  • Adli M; Northwestern University Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Chicago, IL 60611, USA. Electronic address: adli@northwestern.edu.
Dev Cell ; 57(11): 1331-1346.e9, 2022 06 06.
Article en En | MEDLINE | ID: mdl-35508175
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factores de Transcripción / Carcinoma Ductal Pancreático / Proteínas con Homeodominio LIM / Proteínas del Tejido Nervioso Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factores de Transcripción / Carcinoma Ductal Pancreático / Proteínas con Homeodominio LIM / Proteínas del Tejido Nervioso Límite: Humans Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos