TFAP4/DLGAP5 promotes tumor progression and macrophage M2 polarization in prostate cancer by activating the JAK2/STAT3 signaling

Background

M2-polarized macrophages exhibit pro-tumorigenic functions in multiple malignancies, including prostate cancer (PC). Discs large homolog-associated protein 5 (DLGAP5) acts as an oncogenic driver in PC. This study aims to delineate the precise role and mechanistic basis of DLGAP5 in regulating PC-associated macrophage polarization.

Methods

Bioinformatics analyses were used to observe the expression profiling and polarization association of DLGAP5 and its upstream transcription factors (TFs). Cell phenotypes were assessed by measuring cell invasion, migration, apoptosis, and proliferation. After co-culture with PC cells, M2 macrophage polarization was evaluated by measuring M2-associated markers through quantitative PCR, Western blot, and flow cytometry. Xenograft tumor models were employed to validate the oncogenic role of DLGAP5 in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirmed the functional interaction between transcription factor AP-4 (TFAP4) and the DLGAP5 promoter.

Results

DLGAP5 and TFAP4 were upregulated in PC tumors and cell lines. Elevated DLGAP5 expression was significantly associated with higher Gleason score, advanced clinical stage, and worse prognosis. Depletion of DLGAP5 suppressed cell growth, migration, and invasion capacities in vitro. Moreover, DLGAP5 depletion attenuated the M2 polarization of PC-associated macrophages. Also, knockdown of DLGAP5 decreased tumorigenicity and macrophage M2 polarization in vivo. Mechanistically, TFAP4 transcriptionally activated the DLGAP5 promoter to upregulate DLGAP5 expression. Loss of TFAP4 suppressed tumor cell growth, migratory capacity, and invasiveness, as well as macrophage M2 polarization, all of which could be rescued through DLGAP5 re-expression. Additionally, TFAP4 activated the JAK2/STAT3 signaling through DLGAP5 in PC cells. Inhibition of JAK2/STAT3 signaling reversed DLGAP5-mediated malignant phenotypes and macrophage M2 polarization.

Conclusion

Our findings demonstrate that TFAP4-transcriptionally activated DLGAP5 drives PC progression by promoting tumorigenic properties and macrophage M2 polarization, establishing the TFAP4/DLGAP5 axis as a potential therapeutic target for PC.