Background Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. Methods Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid–liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. Results YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. Conclusions Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer–promoter interactions, thereby increasing PCa progression.

Objective: Human Epidermal Growth Factor Receptor 2 (HER2) is highly expressed in multiple malignancies and associated with patients’ prognosis, but its role in bladder cancer (BCa) remains elusive. We conducted this meta-analysis to explore the clinical significance and prognostic value of HER2 in BCa. Methods: PubMed was searched for studies published between January 1, 2000 and January 1, 2020. The odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95%CIs) were used to investigate the relationship between HER2 and BCa pathological features. TCGA was mined for the information regarding as well. Results: Our study included 14 articles enrolling 1398 people. Expression of HER2 is higher in bladder cancer than in normal tissues. HER2 over-expression is associated with CIS, multifocal tumor, large tumor size, high tumor stage and grade, lymph node metastasis, progression, recurrence and papillary tumor. We could not find a significant association between HER2 expression and survival time in BCa patients. Conclusions: Our meta and bioinformatic analysis indicated that HER2 expression was related to pathological malignancy and poor prognosis in BCa.

Immune checkpoint therapy for prostate cancer (PCa), a classic ‘immune-cold’ tumor characterized by an immunosuppressive tumor microenvironment, failed previously in clinical trials, but the underlying causes remain elusive. Here we find that YY1⁺, immunosuppressive macrophages aggregate in the hypoxic areas of PCa. Mechanistically, hypoxia promotes the phase separation of YY1 in the nucleus, where YY1 binds to NUSAP1 and promotes the SUMOylation, phase separation and stabilization of HIF-1α. Either myeloid-specific conditional knockout of YY1 or a treatment with tenapanor for decreasing the YY1–NUSAP1–HIF-1α interaction impairs subcutaneous PCa tumor formation in mouse prostate tumor models. Lastly, a first-generation tetrahedral DNA nanostructure based on the proteolysis targeting chimera technique, termed YY1-DcTAC, allows targeting and degrading YY1 in tumor-associated macrophages for inducing antitumor effects and CD8⁺ T cell tumor infiltration in mouse tumor models. In summary, our findings underscore the pivotal role of YY1 in the hypoxia/HIF-1α pathway in tumor-associated macrophages and support the targeting of YY1 for treating PCa.

Enhancer release and retargeting (ERR) events could activate disease-causing gene promoters for increasing the expression level of oncogenes. Meanwhile, class A orphan GPCRs (oGPCRs) are known as potential biomarkers or drug targets for various cancers, such as gastric cancer (GC). Hence, systemic investigation of ERR events for class A oGPCRs in GC could help to explore biomarkers for GC. In this study, ENCODE and GTEx eQTL data were utilized to define ERR events in GC. Only GPR35 was then detected that could be activated by ERR in GC based on these data and ChIP-seq. Then, activated GPR35 functional in GC cells were explored by flow cytometry, cell-based wound healing assay, Transwell migration assay, and M2 polarization of macrophages assay. Meanwhile, according to TCGA and GEO database, overall survival, immune-related gene expression, and immune cell infiltration level in different GPR35 expressions were calculated. Here, we found ERR event activate GPR35 results in GC cells proliferation and migration, and partly immune cells significance exhaustion (CD8 + T-cells and CD4 + memory T-cells) and/or infiltration (T-cells and macrophage). Meanwhile, high GRP35 level leads to a poor prognosis in GC patients, probably partly due to it promoting the immune infiltration level of macrophages and then inducing polarization of M2 macrophages. Notably, GPR35’s high expression in CTSB+ and CD68 + macrophage could be a genetic indicator for early warning of primary GC. Hence, our findings provide a novel activation approach for oGPCRs, and GPR35 could be determined as a new drugable receptor and early genetic indicator for GC.

Circular RNAs (circRNAs) have been demonstrated to play vital roles in cancer development and progression. However, studies on the association between circRNAs and prostate cancer (PCa) are still lacking. CircRNA sequencing of two pairs of PCa tissues and adjacent normal tissues was conducted in the present study, and qRT–PCR was performed to verify the results. Functional experiments were performed to investigate cellular functions after specific changes. Mass spectrometry analysis after RNA pull-down experiments and Co-IP assays were further conducted. Downstream target proteins were predicted via online databases and detected in vitro by Western blot analysis and in vivo by immunohistochemistry. Hsa_circ_0006156 (subsequently named circ_0006156) expresses at low levels in both PCa tissues and cells, and it significantly inhibits the migration and invasion of PCa cells. Circ_0006156 binds to and blocks the ubiquitination of S100A9. Moreover, functional assays revealed that circ_0006156 represses the malignant progression of PCa by binding to S100A9. Finally, in vivo experiments showed that circ_0006156 suppresses PCa migration and invasion by increasing S100A9, revealing circ_0006156 as a potential novel effective target for PCa treatment.