Targeting the JMJD6/TGF-β axis in prostate cancer by immunotherapy: A potential treatment based on RNA splicing

Abstract

Prostate cancer showcases remarkable clinical heterogeneity. Long-term treatment targeting androgen/androgen receptor-axis may drive patients to develop castration-resistant and more aggressive neuroendocrine phenotypes. The tumor immune microenvironment (TIME) presents activation of multiple progression-related programs. It is generally considered that TGFβ secreted by prostate cancer cell leads to inhibitory activity of effector T lymphocytes and contributes to inhibitory TIME by activation of TGFβ signaling pathway. However, the mechanisms regulating mRNA splicing and expression of TGFβ are poorly understood. Here we hypothesize that Jumonji domain-containing 6 (JMJD6), previously as a histone demethylase, underlies the function of aiding alternative splicing of TGFβ mRNA, which promote TGFβ production and secretion, and activate TGFβ signal pathway from upstream links, eventually forming immunosuppressive TIME and inducing therapeutic resistance. We identify that JMJD6 interacts with multiple splicing cofactors including serine/arginine enriched splicing factor 8 (SRSF8), heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) and heterogeneous nuclear ribonucleoprotein K (HNRNPK) based on mass spectrometry analysis. Moreover, the obviously positive relationships occur among JMJD6, SRSF8/HNRNPA2B1/HNRNPK and TGFβ based on database analysis. In view of limited clinical efficacies of using neutralizing antibody of TGFβ, TGFβ receptor inhibitor and TGF-β/PD-L1 coupled antibodies targeting TGFβ signal pathway and delaying tumor progression, our data provide a novel therapeutic insight on blocking TGFβ production from transcription/mRNA splicing level through targeting JMJD6. Our results suggest that targeting the JMJD6/TGF-β Axis can combine with immunotherapies targeting TGFβ signal pathway in TIME to achieve great benefits for treating prostate cancer progression. Combination with JMJD6 antagonist and immunotherapy can sensitize the anti-tumor effect produced by targeting TGFβ signal pathway, block the production of TGFβ from the origin and solve the bottleneck of immunotherapy for prostate cancer.