<p>Prostate
cancer is (PCa) the second leading cause of cancer death in males in the United
State, with 174,650 new cases and 31,620 deaths estimated in 2019. Polo-like
kinase 1 (PLK1) has been postulated to have a pro-tumorigenesis function,
besides its critical role in regulation of cell cycle, and to be overexpressed
in various types of human cancer, including prostate cancer (PCa). However, our
understanding remains unclear regarding the pro-tumor properties of PLK1
partially due to a lack of proper animal model. Integrating our recently
generated prostate-specific PLK1 knock-in genetically engineered mouse model
(GEM) and the transcriptome data of human PCa patients, we identify an
oncogenic role of PLK1 in the prostate adenocarcinoma progression, castration
resistance and metastatic dissemination.
To elucidate the underlying mechanism, we investigate the link between
PLK1 and tumor microenvironment in PCa using the transgenic mouse model, and
find that PLK1overexpression enable the macrophages polarization towards M2
phenotype via driving the activation of IL4/IL13/STAT6 pathway. These findings
first validates PLK1 as a critical oncogene closely associated with PCa
progression in vivo, and uncover a novel function of PLK1 to facilitate
IL4/STAT6 signaling and M2 macrophage polarization. Importantly, these findings
suggest an efficient therapeutic strategy targeting STAT6 for treatment of
advanced PCa which usually possessing a high level of PLK1 expression. To
further explore the molecular mechanism underlying PLK1-induced PCa progression
and resistance to therapy, we turned our eyes to epigenetic modifications. It
has been documented that epigenetic deregulation such as histone modification
and DNA methylation contributes to PCa initiation and progression. Enhancer of
zeste homologue 2 (EZH2), the catalytic subunit of Polycomb-repressive complex
2 (PRC2), plays a critical role in repressing gene expression by
tri-methylation of histone 3 at lysine 27 (H3K27me3). Emerging data have
demonstrated that there is a link between EZH2 and oncogenesis as EZH2-mediated
methylation acts as an important factor in epigenetic silencing of tumor
suppressor genes in cancer. Expression
of EZH2 is often upregulated in castration-resistant prestate cancer (CRPC),
thus EZH2 has been proposed as a target for CRPC. Importantly, it has been
demonstrated that EZH2 becomes hyperphosphorylated in CPRC cells. Further, it
has been shown that the oncogenic function of EZH2 is usually regulated by the
post-translational modifications. PLK1 acting as a serine/threonine kinase to
regulate multiple signaling pathways in human cancer, however, whether PLK1 is
involved in EZH2 phosphorylation is not known. Herein, we show that Plk1
physically interacts with EZH2 and negatively regulates H3K27 trimethylation (H3K27me3).
Furthermore, Plk1 can phosphorylate EZH2 at T144, and Plk1-mediated phosphorylation
of EZH2 is involved in inhibiting EZH2 activity toward H3K27me3. More
importantly, EZH2 phosphorylation by Plk1 is inhibitory for PRC2-mediated gene
repression but required for transcriptional activation toward oncogenesis.
Finally, by combination with Plk1 inhibitor BI2536, we show a robust
sensitization of EZH2 inhibitors in CRPC cell lines, as well as in CRPC
xenograft tumors. Our findings provide a new mechanism to define the oncogenic
activity of EZH2 and suggest that inhibition of Plk1-mediated EZH2 activity may
provide a promising therapeutic approach for CRPC.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/11320049 |
| Date | 05 December 2019 |
| Creators | Ruixin Wang (8082788) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/A_Novel_Mechanism_for_Prostate_Cancer_Progression_from_Polo-like_Kinase_1_to_Epigenetics/11320049 |
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