Function and Mechanism of Alkbh5 In N6-Methyl-Adenosine Rna Modification In Glioblastoma

<p>N⁶-methyl-adenosine (m⁶A) is the most prevalent internal chemical modification of mRNAs in eukaryotes. In mammals, m⁶A installed by m⁶A methyltransferases METTL3 and METTL14 is erased by two members of the AlkB family of nonheme Fe(II)/a-ketoglutarate (a-KG)-dependent dioxygenases, fat-mass and obesity associated protein (FTO) or ALKBH5. ALKBH5 affects nuclear RNA export and metabolism, gene expression and mouse fertility. To date, little is known about the biological significance of m⁶A in human cancer. We found that ALKBH5 is highly expressed in human glioblastoma stem cells which are resistant to conventional therapy and give rise to glioblastoma recurrence by sustaining long-term tumor growth. Global manipulation of the m⁶A modification by depleting ALKBH5 resulted in altered gene expression including subsets of genes enriched in “Cell Cycle”, “DNA Replication, Recombination, and Repair” and “Cellular Assembly and Organization”. Knockdown of ALKBH5 expression in human glioblastoma stem cells significantly reduced their self-renewal ability as a result of inhibition of cell cycle progression. Depleting ALKBH5 reduced expression of Nestin and SOX2, NANOG, OCT4, the core transcription factors that endow tumor cells with self-renewal capacity. This study demonstrated the important role of m⁶A modification in human glioblastoma development.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• Zhang, Sicong

Contributors dc:contributor

• Suyun Huang
• Oliver Bogler, Ph.D.
• Richard R. Behringer, Ph.D

• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/698

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1742