Date of Graduation
8-2016
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Suyun Huang
Committee Member
Oliver Bogler, Ph.D.
Committee Member
Richard R. Behringer, Ph.D
Committee Member
Richard R. Behringer, Ph.D.
Committee Member
Sadhan Majumder, Ph.D.
Committee Member
Xiaoping Sun, M.D., Ph.D.
Committee Member
Zhen Fan. M.D.
Abstract
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.