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PKM2-EZH2 INTERACTION ELICITS METABOLIC VULNERABILITY FOR TREATMENT OF TRIPLE- NEGATIVE BREAST CANCER

thesis
posted on 07.05.2020 by Yingsheng Zhang

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 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.

Furthermore, Dendritic Cell (DC) vaccination has shown promise in treating cancer patients. However, the in vitro 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.

History

Degree Type

Doctor of Philosophy

Department

Animal Sciences

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Alice Chang

Advisor/Supervisor/Committee co-chair

Shihuan Kuang

Additional Committee Member 2

Michael Wendt

Additional Committee Member 3

Guangjun Zhang

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