PTTG1-mediated reprogramming of asparagine metabolism enhances DNA damage repair and leads to compromised antitumor immunity in prostate cancer.

Abstract

Background: CD8⁺T cell dysfunction is a key factor in immune escape of prostate cancer (PCa). While pituitary tumor-transforming gene 1 (PTTG1) exhibits oncogenic effects in multiple cancers, its role in PCa immunoregulation remains unclear.

Methods: Bioinformatics analysis of TCGA data evaluated PTTG1 expression, prognosis, and CD8⁺T cell infiltration. qRT-PCR and western blot (WB) assessed PTTG1 levels in PCa cells. CD8⁺T cell cytotoxicity was measured via LDH release and ELISA (GZMB/TNF-α/IFN-γ). DNA damage was quantified by comet assay and γ-H2AX immunofluorescence. The metabolism of asparagine (Asn) was evaluated by detecting the content of Asn through a kit and the expression of asparagine synthase (ASNS) through WB. A mouse model of allograft tumor was constructed, and the mechanism was verified by immunohistochemistry (PTTG1, ASNS, γ-H2AX, KI67) and flow cytometry detection (proportion of CD8⁺T cells).

Results: Bioinformatics analysis revealed that PTTG1 was highly expressed in PCa, positively correlated with the poor prognosis of patients, and negatively correlated with CD8⁺T cell infiltration. Cell experiments further demonstrated that PTTG1 inhibited the killing effect of CD8⁺T cells on PCa cells. In addition, in vitro and in vivo experiments showed that PTTG1 promoted DNA damage repair (DDR) of PCa by reprogramming Asn, and targeting PTTG1 enhanced the anti-tumor activity of CD8⁺T cells.

Conclusion: PTTG1 promotes DDR by reprogramming Asn metabolism, thereby inhibiting the function of CD8⁺T cells. Targeting PTTG1 can reverse this process, providing a new strategy for PCa immunotherapy.