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Integrin ?6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells.

ABSTRACT: Both the extracellular matrix (ECM) and DNA epigenetic regulation are critical for maintaining stem cell phenotype and cancer progression. Whether and how ECM regulates epigenetic alterations to influence cancer stem cells (CSCs) remain to be explored. Here we report that ECM through laminin-integrin ?6 upregulates ten-eleven translocation enzyme 3 (TET3) dioxygenase. TET3 in turn mediates DNA cytosine 5'-hydroxymethylation (5hmC) and upregulates genes critical for maintenance of glioma stem cells (GSCs). Activating integrin ?6-FAK pathway increases STAT3 activity, TET3 expression and 5hmC levels in GSCs. Moreover, targeting STAT3 disrupts integrin ?6-FAK signaling and inhibits TET3+ GSC maturation in vivo. STAT3 directly regulates TET3 expression and the two proteins are co-localized with 5hmC in GSC clusters. 5hmC is upregulated by STAT3 at the promoters of several tumorigenic genes, including c-Myc, known to be critical for GSCs. In vivo silencing of TET3 in GSC-enriched tumors reduces 5hmC accumulation and expression of the GSC critical genes, leading to tumor growth inhibition. TET3 expression and 5hmC accumulation also co-segregate with integrin ?6 in patient malignant glioma. Thus, ECM- integrin ?6-STAT3-TET3 axis regulates hydroxymethylation of genes important for GSCs, thereby increasing GSC tumorigenicity and resistance to therapies.

SUBMITTER: Herrmann A

PROVIDER: S-EPMC7060098 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells.

Herrmann Andreas A Lahtz Christoph C Song Jieun J Aftabizadeh Maryam M Cherryholmes Gregory A GA Xin Hong H Adamus Tomasz T Lee Heehyoung H Grunert David D Armstrong Brian B Chu Peiguo P Brown Christine C Lim Michael M Forman Stephen S Yu Hua H

Oncogene 20191209 10

Both the extracellular matrix (ECM) and DNA epigenetic regulation are critical for maintaining stem cell phenotype and cancer progression. Whether and how ECM regulates epigenetic alterations to influence cancer stem cells (CSCs) remain to be explored. Here we report that ECM through laminin-integrin α6 upregulates ten-eleven translocation enzyme 3 (TET3) dioxygenase. TET3 in turn mediates DNA cytosine 5'-hydroxymethylation (5hmC) and upregulates genes critical for maintenance of glioma stem cel ...[more]

PMID: 31819166

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Project description:Significance statementEpigenetic changes have been proposed to mediate nephron endowment during development, a critical determinant of future renal disease development. Hydroxymethyl cytosine, an epigenetic modification important for gene regulation, is abundant in the human kidney, but its physiologic role and the role of DNA demethylase enzymes encoded by the Tet1 , Tet2 , or Tet3 , which mediate cytosine hydroxymethylation, are unclear. By genetically deleting Tet1 , Tet2 , or Tet3 in nephron progenitors in mice, the authors showed that combined Tet2 and Tet3 loss in nephron progenitors cause defective kidney development, leading to kidney failure and perinatal death. Tet2 and Tet3 deletion also caused an alteration in demethylation and expression of genes critical for nephron formation. These findings establish that Tet2- and Tet3 -mediated cytosine hydroxymethylation in nephron progenitors plays a critical role in nephron endowment.BackgroundNephron endowment is a key determinant of hypertension and renal disease in later life. Epigenetic changes have been proposed to mediate fetal programming and nephron number. DNA cytosine methylation, which plays a critical role in gene regulation, is affected by proteins encoded by the ten-eleven translocation (TET) DNA demethylase gene family ( Tet1 , Tet2 , and Tet3 ), but the roles of TET proteins in kidney development and nephron endowment have not been characterized .MethodsTo study whether epigenetic changes-specifically, active DNA hydroxymethylation mediated by Tet1 , Tet2 , and Tet3- are necessary for nephron progenitor differentiation and nephron endowment, we generated mice with deletion of Tet1 , Tet2 , or Tet3 in Six2-positive nephron progenitors cells (NPCs). We then performed unbiased omics profiling, including whole-genome bisulfite sequencing on isolated Six2-positive NPCs and single-cell RNA sequencing on kidneys from newborn mice.ResultsWe did not observe changes in kidney development or function in mice with NPC-specific deletion of Tet1 , Tet2 , Tet3 or Tet1 / Tet2 , or Tet1 / Tet3 . On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons, leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2 -positive NPCs resulted in defective mesenchymal to epithelial transition and renal vesicle differentiation. Whole-genome bisulfite sequencing, single-cell RNA sequencing, and gene and protein expression analysis identified a defect in expression in multiple genes, including the WNT- β -catenin signaling pathway, due to a failure in demethylation of these loci in the absence of Tet2 and Tet3 .ConclusionsThese findings suggest that Tet2- and Tet3 -mediated active cytosine hydroxymethylation in NPCs play a key role in kidney development and nephron endowment.

Dataset Information

Integrin ?6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells.

Publications

Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells.

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