한빛사 논문
Andreas Herrmann1,2,*, Christoph Lahtz1,2, Jieun Song1, Maryam Aftabizadeh1, Gregory A. Cherryholmes1, Hong Xin1, Tomasz Adamus1,2, Heehyoung Lee1, David Grunert1, Brian Armstrong3, Peiguo Chu4, Christine Brown5, Michael Lim6, Stephen Forman5, Hua Yu1,*
1Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
2 Sorrento Therapeutics, San Diego, CA 92121, USA
3 Department of Neuroscience, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
4 Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
5 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
6 Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287, USA
These authors contributed equally: Andreas Herrmann, Christoph Lahtz, Jieun Song
*Corresponding author
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.
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