A research team led by Prof. WANG Hongzhi at the Hefei Institutes of Physical Science, Chinese Academy of Sciences, has uncovered a previously unrecognized role of prostaglandin E synthase 3 (PTGES3) in liver cancer, revealing how it drives both tumor growth and immune suppression.
The study was recently published in Molecular Biomedicine.
Traditionally known as a cytoplasmic co-chaperone of HSP90, PTGES3 was found to function as a nuclear transcriptional regulator in this study.
In this study, however, it is identified as a nuclear transcriptional regulator. Further analyses showed that PTGES3 is significantly overexpressed in HCC and is independently associated with poor prognosis.
Functional assays demonstrated that PTGES3 promotes HCC cell proliferation and migration via the PI3K/AKT/mTOR pathway. In a diethylnitrosamine (DEN)-induced mouse model, hepatocyte-specific knockdown of Ptges3 markedly suppressed tumor growth. In addition, single-cell RNA sequencing revealed that reduced Ptges3 expression reshapes the tumor immune microenvironment, characterized by decreased M2 macrophage polarization.
Mechanistically, PTGES3 directly binds to a G-rich motif in the SP1 promoter in the nucleus, thereby activating SP1 transcription. This leads to increased TGF-β secretion, which not only sustains tumor proliferation through autocrine activation of the PI3K/AKT/mTOR pathway but also promotes M2 macrophage polarization via paracrine signaling. Notably, this effect is not reversed by HSP90 inhibition but can be effectively blocked by a TGF-β receptor inhibitor, indicating that the function is independent of PTGES3’s classical chaperone activity.
The findings identify the PTGES3/SP1/TGF-β axis as a potential therapeutic target, offering new strategies for combining targeted therapy with immunotherapy in liver cancer.
Schematic illustration showing the novel mechanism by which PTGES3 nuclear transcriptional regulation promotes hepatocellular carcinoma proliferation and immunosuppression. (Image by WANG Nianfei)
