<p>Triple Negative Breast
Cancer (TNBC) is the most aggressive type of breast cancer. TNBC patients are
resistant to virtually all target therapies and suffer a higher post-chemotherapy
relapse with a worse overall survival compared with other types of breast
cancers. Therefore, the development of an effective therapy is urgently needed.
PKM2 plays a prominent role in mediating<b>
</b>tumor glycolysis and PKM2 is often overexpressed in human cancers. However,
whether PKM2 mediated glycolysis is necessary for cancer cell growth is
questionable. Here, I have found that inhibition of PKM2 does not affect TNBC cell
growth due to a metabolic switch from glycolysis to fatty acid oxidation (FAO).
We show that PKM2 directly interacts with EZH2 to coordinately mediate
epigenetic silencing of SLC16A9, transporter of a key player in FAO, Carnitine.
Inhibition of either PKM2 or EZH2 increases levels of SLC16A9 and intracellular
Carnitine to promote FAO and thereby sustains cancer cell growth. Direct
inhibition of EZH2 using a clinically tested EZH2 inhibitor, GSK126, is able to
elicit a previously unidentified vulnerability to a clinically tested FAO
inhibitor, Etomoxir. As a result, combined GSK126-Etomoxir treatment
synergistically abolishes TNBC xenograft tumor growth in vivo. Together, this
study uncovers PKM2-EZH2 mediated metabolic reprogramming that leads to a new
drug combination therapy by dual targeting of EZH2 and FAO for effective
treatment of TNBC.<b>
</b></p>
<p> </p>
<p>Furthermore, Dendritic Cell
(DC) vaccination has shown promise in treating cancer patients. However, the <i>in
vitro</i> generation of a fully functional DC remains a big challenge in this
field. EZH2 inhibition has shown to be able to create an immunologically ‘hot’ tumors.
Nonetheless, the role of EZH2 in regulation of DC function is still unclear. I
found that the expression levels of EZH2 and its functional maker, H3K27Me3,
are enhanced following maturation from immature DC (iDC) into two functional
DCs, α-type 1-polarized-DC
(αDC) and gold
standard DC (sDC). Moreover, inhibition of EZH2 by GSK126 treatment elicits a
dependency of sDC on FAO.
These results suggest that EZH2 plays a role in maturation of DC through metabolic
reprogramming, which may also provide new DC based immunotherapy of
TNBC. </p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12249971 |
| Date | 07 May 2020 |
| Creators | Yingsheng Zhang (8801084) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/PKM2-EZH2_INTERACTION_ELICITS_METABOLIC_VULNERABILITY_FOR_TREATMENT_OF_TRIPLE-_NEGATIVE_BREAST_CANCER/12249971 |
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