STAT3 Regulates Glioblastoma Stem Cell Multipotency Through an Epigenetic Mechanism.
Glioblastoma multiforme (GBM) is a deadly brain tumor with a median post-diagnosis
survival time of only 14.6 months. The current clinical standard of care does not
prevent glioblastoma recurrence, and novel therapies are critical to increasing the
survival of glioblastoma patients. Recently it has become clear that there is a small
population of cells in GBM known as tumor stem ... read morecells that harbor most of the tumorigenic
potential and likely account for the resistance of the tumor to therapy. Glioblastoma
stem cells can be isolated and propagated as cell lines from primary tumor samples.
These cells can self-renew and differentiate, and are highly tumorigenic. STAT3 is a
signaling molecule that is activated by many cytokines and growth factors. It is
constitutively activated in many human cancers, including glioblastoma. In Chapter 2 of
this dissertation, I describe a role for STAT3 in regulating the proliferation and
differentiation of glioblastoma stem cells. I demonstrate that STAT3 is critical for the
expression of stem cell markers in glioblastoma stem cells, and that STAT3 inhibition
induces a partial differentiation. STAT3 inhibition decreases neurosphere formation of
glioblastoma stem cells, and this phenotype is not reversible. In Chapter 3, I
investigate the mechanism by which STAT3 maintains multipotency in GBM-SC. I have found
that STAT3 represses the H3K27 demethylase Jmjd3 in glioblastoma stem cells. Jmjd3
opposes the activity of the polycomb repressor complex 2 (PRC2), which establishes gene
repression via H3K27 methylation. I find that Jmjd3 repression by STAT3 is necessary for
neurosphere formation. STAT3 binds to the Jmjd3 promoter, suggesting that this
regulation is direct. STAT3 regulation of Jmjd3 is conserved in neural stem cells
derived from human embryonic stem cells. Together these data suggest that STAT3
perpetuates glioblastoma and neural stem cell self-renewal in part by repressing Jmjd3
expression. In Chapter 4, I show that several additional histone epigenetic modifiers
also have an effect on glioblastoma stem cell growth. EED and EZH2, both components of
PRC2, were found to be necessary for growth. In addition, EED knockdown leads to the
induction of a neuronal marker, while EZH2 may promote survival of glioblastoma stem
cells. I find that EHMT2, an H3K9 methylase, is also important for GBM-SC growth.. These
data suggest that that EED, EZH2, and EHMT2 may be therapeutic targets for glioblastoma.
In summary, this dissertation presents findings that support the hypothesis that STAT3
is required for tumor stem cell function in glioblastoma. I also show that STAT3
repression of Jmjd3 is necessary for maintenance of multipotency of both glioblastoma
and normal neural stem cells. Together these data suggest the STAT3 could be an
effective target for glioblastoma therapy.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Brent Cochran.
Committee: Daniel Jay, Gary Sahagian, James Schwob, and Yang Shi.
Keyword: Physiology.read less