YY1 enhances HIF-1α stability in tumor-associated macrophages to suppress anti-tumor immunity of prostate cancer

Prostate cancer, as an immune-cold tumor, shows poor response to immune
checkpoint inhibitors, but the underlying mechanisms are not fully
understood. Through YY1 proteomics experiments and RNA sequencing of THP-1
cells overexpressing YY1, combined with other biomolecular experiments, we
demonstrated that hypoxia promotes the phosphorylation of YY1, thereby
enhancing its binding to NUSAP1 and stabilizing HIF-1α, which in turn
regulates the tumor microenvironment. Through bioinformatics techniques
and in vitro protein IP experiments, we clarified that in tumor-associated
macrophages, Tenapanor can competitively bind to the site to block the
interaction between YY1 and NUSAP1, thereby affecting the stability of
HIF-1α. To verify the therapeutic effects and mechanisms of Tenapanor on
prostate cancer, we used the prostate cancer cell line RM1 to induce
subcutaneous tumors in C57BL/6 mice. One week after tumor implantation, we
administered TEN-M2pep or NC-M2pep (Tenapanor or control solvent linked to
TAM-targeting peptide M2pep) via tail vein injection to the experimental
group (n=3) and control group mice (n=3). After 24 days, we harvested the
subcutaneous tumors, ground them, and digested them into single-cell
suspensions. We then performed bulk RNA sequencing on the CD45-selected
cells. Additionally, to degrade YY1, we constructed YY1-targeted
tetrahedral DNA-caged PROTACs (YY1-DcTACs) and performed single-cell
sequencing on subcutaneous tumors from mice injected with YY1-DcTACs and
NC-DcTACs via tail vein injection. The combination of both sequencing
results, along with further studies using immunohistochemistry and flow
cytometry, demonstrated that inhibiting the YY1-NUSAP1 interaction or
targeting the degradation of YY1 can promote T cell proliferation and
activation, as well as the enrichment of immune response-related pathways
in subcutaneous tumors, and enhance the infiltration of CD8+ T cells.
These research findings demonstrate that targeting macrophage YY1 is a
potential therapeutic strategy for treating prostate cancer and promoting
tumor immunity.