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

Andreas Herrmann, Christoph Lahtz, Jieun Song, Maryam Aftabizadeh, Gregory A. Cherryholmes, Hong Xin, Tomasz Adamus, Heehyoung Lee, David Grunert, Brian Armstrong, Peiguo Chu, Christine Brown, Michael Lim, Stephen Forman, Hua Yu

Research output: Contribution to journalArticle

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 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 cells (GSCs). Activating integrin α6-FAK pathway increases STAT3 activity, TET3 expression and 5hmC levels in GSCs. Moreover, targeting STAT3 disrupts integrin α6-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 α6 in patient malignant glioma. Thus, ECM- integrin α6-STAT3-TET3 axis regulates hydroxymethylation of genes important for GSCs, thereby increasing GSC tumorigenicity and resistance to therapies.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Integrins
Glioma
Stem Cells
Maintenance
Enzymes
Genes
Extracellular Matrix
Neoplastic Stem Cells
Epigenomics
Up-Regulation
Dioxygenases
myc Genes
Cytosine
DNA
Phenotype
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Herrmann, A., Lahtz, C., Song, J., Aftabizadeh, M., Cherryholmes, G. A., Xin, H., ... Yu, H. (Accepted/In press). Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells. Oncogene. https://doi.org/10.1038/s41388-019-1134-6

Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells. / Herrmann, Andreas; Lahtz, Christoph; Song, Jieun; Aftabizadeh, Maryam; Cherryholmes, Gregory A.; Xin, Hong; Adamus, Tomasz; Lee, Heehyoung; Grunert, David; Armstrong, Brian; Chu, Peiguo; Brown, Christine; Lim, Michael; Forman, Stephen; Yu, Hua.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Herrmann, A, Lahtz, C, Song, J, Aftabizadeh, M, Cherryholmes, GA, Xin, H, Adamus, T, Lee, H, Grunert, D, Armstrong, B, Chu, P, Brown, C, Lim, M, Forman, S & Yu, H 2019, 'Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells', Oncogene. https://doi.org/10.1038/s41388-019-1134-6
Herrmann, Andreas ; Lahtz, Christoph ; Song, Jieun ; Aftabizadeh, Maryam ; Cherryholmes, Gregory A. ; Xin, Hong ; Adamus, Tomasz ; Lee, Heehyoung ; Grunert, David ; Armstrong, Brian ; Chu, Peiguo ; Brown, Christine ; Lim, Michael ; Forman, Stephen ; Yu, Hua. / Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells. In: Oncogene. 2019.
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AU - Aftabizadeh, Maryam

AU - Cherryholmes, Gregory A.

AU - Xin, Hong

AU - Adamus, Tomasz

AU - Lee, Heehyoung

AU - Grunert, David

AU - Armstrong, Brian

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AU - Brown, Christine

AU - Lim, Michael

AU - Forman, Stephen

AU - Yu, Hua

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