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

被引：12

作者：

Ozturk, Harun ^{[1
]}

Cingoz, Harun ^{[1
]}

Tufan, Turan ^{[2
]}

Yang, Jiekun ^{[2
]}

Adair, Sara J. ^{[4
]}

Tummala, Krishna Seshu ^{[3
]}

Kuscu, Cem ^{[2
]}

Kinali, Meric ^{[1
]}

Comertpay, Gamze ^{[5
]}

Nagdas, Sarbajeet

Goudreau, Bernadette J. ^{[4
]}

Luleyap, Husnu Umit ^{[5
]}

Bingul, Yagmur ^{[1
]}

Ware, Timothy B.

Hwang, Wiliam L. ^{[3
]}

Hsu, Ku-lung ^{[7
]}

Kashatus, David F. ^{[6
]}

Ting, David T. ^{[3
]}

Chandel, Navdeep S. ^{[8
,9
]}

Bardeesy, Nabeel ^{[3
]}

Bauer, Todd W. ^{[4
]}

Adli, Mazhar ^{[1
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Robert Lurie Comprehens Canc Ctr, Dept Obstet & Gynecol, Chicago, IL 60611 USA

[2] Univ Virginia, Dept Biochem & Mol Genet, Sch Med, Charlottesville, VA 22903 USA

[3] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA

[4] Univ Virginia, Dept Surg, Sch Med, Charlottesville, VA 22903 USA

[5] Cukurova Univ, TR-01330 Adana, Turkey

[6] Univ Virginia, Dept Cell Immunol & Canc Biol, Sch Med, Charlottesville, VA 22903 USA

[7] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA

[8] Northwestern Univ, Feinberg Sch Med, Robert Lurie Comprehens Canc Ctr, Dept Pulm & Crit Care, Chicago, IL 60611 USA

[9] Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA

来源：

DEVELOPMENTAL CELL | 2022年 / 57卷 / 11期

关键词：

PPAR-GAMMA; TRANSCRIPTION FACTORS; LIMB-BUD; SUBTYPES; EXPRESSION; CRISPR; GROWTH; CELLS; ADENOCARCINOMA; MIGRATION;

D O I：

10.1016/j.devcel.2022.04.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1331 / +

页数：26

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