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academies
Cell Science, Stem Cell Research &
Pharmacological Regenerative Medicine
November 29-30, 2017 | Atlanta, USA
Annual Congress on
Adv cel sci tissue cul 2017 | Volume 1 Issue 2
Epigenetic regulation of bone metastasis and osteoclast differentiation
Woojin An
University of Southern California, USA
O
steoclasts are multinucleated bone-resorbing cells and
generated by the fusion of mononuclear precursor cells
of the monocyte-macrophage lineage. A group of genes
regulating osteoclast differentiation positively or negatively
have been identified and the deregulated expression of
these genes has been documented to cause various skeletal
diseases. MMP-9 is a member of MMP family that has been
studied mainly with respect to its role in extracellular matrix
remodeling. Unexpectedly, however, we found that MMP-9
moves into the nucleus and mediates histone H3 N-terminal
tail proteolysis at osteoclastogenic genes in RANKL-induced
osteoclast precursor (OCP) cells. Our observation that MMP-
9 knockdown abrogates H3 N-terminal tail proteolysis and
osteoclastogenicgeneexpressionissupportiveoftheideathat
MMP-9 is the major protease responsible for H3 N-terminal
tail proteolysis-mediated gene activation occurring in
OCP-induced cells. Furthermore, our follow-up studies
indicate that specific patterns of histone posttranslational
modification are key regulators of MMP-9 protease activity
toward target chromatin domains in OCP-induced cells.
Cancer cells frequently spread to bone and secrete soluble
signaling factors to accelerate osteoclast differentiation and
bone resorption. Since chromatin signaling and regulatory
factors have been implicated in epigenetic control of cancer
metastasis, we also investigated their possible roles as
modulators of metastatic potential of cancer cells to bone.
We show that specific histone modification and histone
variant tightly regulate cancer bone metastasis and osteoclast
differentiation. The observed effects require epigenetic control
of genes encoding secreted factors that influence cancer cell
metastasis and osteoclast differentiation. Consistent with these
data, osteoclastogenesis and osteoporosis are significantly
affected following the administration of recombinant forms of
secreted factors into mice. More interestingly, our mechanistic
studies reveal that histone modification functionally interacts
with histone variant to alter the expression and functional
properties of metastasis-associated genes in cancer cells in the
bone microenvironment.
Speaker Biography
Woojin An investigates the biological role of chromatin modification and its basic
concept and mechanism of action in gene regulation and cell differentiation. By using
multiple new technologies, his recent studies aremainly directed toward understanding
chromatin reorganization and histone modification-mediated recruitment of novel
regulatory factors to specific target genes.
e:
woojinan@med.usc.edu