In this study, we identified the nuclear receptor TLX (also named NR2E1), as a critical regulator of GSCs. Knockdown of TLX dramatically reduced the self-renewal and tumorigenesis of GSCs. Targeting TLX in vivo by virally delivered shRNA or dendrimer nano-particle delivered siRNA significantly slowed down tumor progression in human GSC-derived xenograft tumor model and enhanced mouse survival. Moreover, we identified Ten eleven translocation 3 (TET3), an epigenetic regulator of DNA methylation, as a tumor suppressor downstream of TLX to regulate GSC growth, self-renewal and tumorigenesis.
In addition to the TLX-TET3 axis, we demonstrated that the N6-methyladenosine (m6A) RNA modification plays a critical role in regulating GSC self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, m 6A writers within the RNA methyltransferase complex, led to increased self-renewal and tumorigenesis of GSCs. Overexpression of METTL3 or inhibition of m6A eraser FTO suppressed GSC growth and self-renewal. Moreover, we have shown that m6A regulated genes (e.g. ADAM19 ) play important roles in regulating GSC growth and self-renewal downstream of the m6A modification. In summary, this study identified the TLX-TET3 axis and the m6A mRNA methylation machinery as promising therapeutic targets for GSCs in glioblastoma. (Abstract shortened by ProQuest.)
|Commitee:||Lin, Ren-Jang, Lu, Qiang, Rich, Jeremy N., Rossi, John J.|
|School:||City of Hope's Irell & Manella Graduate School of Biomedical Sciences|
|School Location:||United States -- California|
|Source:||DAI-B 78/10(E), Dissertation Abstracts International|
|Keywords:||Glioblastoma, Glioblastoma stem cell, N6-methyladenosine, Self-renew, TLX, Ten eleven translocation 3|
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