Dissertation/Thesis Abstract

Nuclear Receptor TLX and Epigenetics in Glioblastoma Stem Cells
by Cui, Qi, Ph.D., City of Hope's Irell & Manella Graduate School of Biomedical Sciences, 2017, 117; 10275636
Abstract (Summary)

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.)

Indexing (document details)
Advisor: Shi, Yanhong
Commitee: Lin, Ren-Jang, Lu, Qiang, Rich, Jeremy N., Rossi, John J.
School: City of Hope's Irell & Manella Graduate School of Biomedical Sciences
Department: Biological Sciences
School Location: United States -- California
Source: DAI-B 78/10(E), Dissertation Abstracts International
Subjects: Biology, Oncology
Keywords: Glioblastoma, Glioblastoma stem cell, N6-methyladenosine, Self-renew, TLX, Ten eleven translocation 3
Publication Number: 10275636
ISBN: 9781369763621