Zhe Hong

The failure of second-generation antiandrogen drugs such as enzalutamide (ENZ) treatment indicates that prostate cancer (PCa) can progress to castration-resistant prostate cancer (CRPC). CRPC is considered the terminal stage of PCa and currently has no effective treatment options due to drug resistance. However, the underlying mechanism of ENZ- resistance in CRPC remains unclear. Here, we conducted a single-cell transcriptomic analysis in combination with a gene module clustering assessment to identify the regulatory genes enriched along the hormone-sensitive PCa and CRPC trajectories. This approach revealed that tripartite motif-containing 17 (TRIM17) is a specific time-dependent gene and key regulator that is expressed at significantly low levels in CRPC cells but at high levels in nonresistant epithelial PCa cells. Analysis of patient-derived clinical specimens and in vitro functional experiments demonstrated that TRIM17 low expression could promote CRPC progression and ENZ resistance. Moreover, TRIM17 activation markedly inhibited CRPC progression and enhanced the sensitivity of CRPC cells to ENZ. Mechanistically, TRIM17 binds to and ubiquitinates B-cell lymphoma-2 (BCL2) directly to mediate its degradation. On the other hand, TRIM17 represses BCL2 by inhibiting p53 degradation by TRIM28. The stabilization of p53 suppresses BCL2 expression and interferes with the abundance and signaling of BCL2 in CRPC cells, further inhibiting CRPC progression and conveying ENZ resensitivity. Importantly, the TRIM17 activator pioglitazone, a registered drug for type 2 diabetes, could synergize with ENZ to reverse ENZ resistance and amplify its cytotoxic effects on CRPC cells. In conclusion, this study identifies a previously undefined function of TRIM17 to modulate ENZ sensitivity and reveals that activation of TRIM17 has great potential as a promising therapeutic strategy for ENZ- resistant PCa, indicating that TRIM17 can serve as a biomarker to guide the treatment of CRPC.

Background: In advanced Prostate Cancer (PCa), metastatic spread and the inevitable emergence of enzalutamide resistance represent major clinical hurdles. Although apolipoprotein L3 (APOL3) is linked to oncogenesis, its precise mechanistic role in PCa progression and antiandrogen resistance, particularly its regulation of the STAT3-DAB2IP axis, remains largely unexplored. Methods: Publicly available clinical datasets were analyzed to evaluate APOL3 expression and its prognostic value. The functional consequences of modulating APOL3 and DAB2IP levels were assessed using in vitro and in vivo PCa models, including an established enzalutamide-resistant cell line (C4-2R). Mechanistic insights into cellular proliferation, motility, angiogenesis, and drug response were derived from RNA sequencing, reciprocal co-immunoprecipitation (Co-IP), and dual-targeting phenotypic assays. Results: APOL3 is significantly upregulated in PCa, strongly correlating with elevated Gleason scores, advanced stage, TP53 mutational status, and poor prognosis. Functionally, APOL3 promotes PCa proliferation, metastasis, and angiogenesis. Mechanistically, APOL3 sustains STAT3 phosphorylation and suppresses the tumor suppressor DAB2IP. Notably, Co-IP assays revealed a direct, bidirectional physical interaction between APOL3 and DAB2IP. Furthermore, we discovered that elevated APOL3 drives enzalutamide resistance not by enhancing classical Androgen Receptor (AR) activity, but by directly binding the Glucocorticoid Receptor (GR). This APOL3-GR complex activates a bypass signaling pathway entirely independent of the AR. While restoring DAB2IP resensitized cells to enzalutamide, it triggered a compensatory upregulation of APOL3. Consequently, concurrent APOL3 knockdown and DAB2IP overexpression yielded a powerful synergistic effect, profoundly dismantling malignant phenotypes, suppressing pro-metastatic markers (p-STAT3, VEGF, SNAIL, MMP2), and restoring enzalutamide sensitivity. Discussion: These findings establish APOL3 as a central driver of prostate cancer metastasis and enzalutamide resistance. APOL3 drives these aggressive phenotypes by directly binding and suppressing DAB2IP to sustain oncogenic STAT3 signaling, and by activating an AR-independent bypass pathway through its physical interaction with the Glucocorticoid Receptor (GR). The enrichment of APOL3 in TP53-mutated and resistant tumors underscores its critical role in tumor plasticity. Consequently, synergistically co-targeting APOL3 alongside DAB2IP restoration represents a highly promising therapeutic strategy to overcome adaptive antiandrogen resistance and halt metastatic progression. Conclusion: APOL3 is a central driver of PCa aggressiveness and enzalutamide resistance, functioning via the direct modulation of the DAB2IP/STAT3 axis and the activation of the GR bypass pathway. Cotargeting APOL3 alongside DAB2IP restoration represents a highly promising, synergistic therapeutic strategy to circumvent adaptive resistance and halt metastatic progression in advanced castration-resistant prostate cancer.

Lung metastases (LMs) are common and clinically significant in kidney cancer, contributing to poor prognosis and limited treatment response. Early detection of patients at high risk for LMs is crucial for developing personalized treatment strategies. This retrospective study included 2652 patients with kidney cancer, pathologically confirmed, from two medical centers between 2000 and 2020. A training cohort (n = 1500) was used to develop a predictive model for LMs based on clinical, pathological, and laboratory variables. Multivariate logistic regression was applied to identify independent predictors, and a nomogram was constructed. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration plots, probability density functions (PDFs), and decision curve analysis (DCA). An external validation cohort (n = 1152) was used to assess generalizability. Family cancer history, advanced T stage, and N nodal stage were identified as independent predictors of LMs. The nomogram demonstrated excellent discrimination in the training cohort (AUC = 0.938) and moderate performance in the validation cohort (AUC = 0.883), outperforming individual variables. Calibration analysis showed good agreement between predicted and observed probabilities. Patients with LMs had significantly worse overall survival than those without (p < 0.001). DCA validated the nomogram's greater clinical value over treat-all or treat-none approaches. This nomogram-based model offers an efficient and accessible tool for the early detection of kidney cancer patients at risk for LMs. It enables individualized risk stratification and may assist in optimizing clinical decision-making and improving patient outcomes. Further prospective validation is warranted.

Prostate cancer (PCa) ranks among the most prevalent malignant tumors worldwide. The pivotal role of competitive endogenous RNA (ceRNA) regulatory networks in numerous cancer types has been underscored. However, the specific characteristics of the ceRNA network in PCa remained unknown. This study aims to elucidate the ceRNA regulatory network associated with phosphatase and tensin homolog (PTEN) and to identify potential prognostic markers for PCa. The Cancer Genome Atlas (TCGA) database was employed to extract the expression patterns of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs). LINC01122-hsa-miR-34c-5p/hsa-miR-449a-TPD52 ceRNA network regarding the prognosis of PCa was explored via bioinformatics analysis. Through correlation analysis, we investigated the LINC01122/TPD52 axis within the ceRNA network, identifying it as a significant clinical prognostic marker for PCa. Subsequent analyses indicated that hypomethylation was responsible for the abnormal upregulation of the LINC01122/TPD52 axis. Furthermore, immune infiltration analysis revealed the impact of the LINC01122/TPD52 axis on the tumor immune microenvironment and the progression of PCa. Finally, a nomogram was constructed to forecast the 1-year, 3-year, and 5-year survival probabilities of PCa patients. In summary, our study demonstrates the significant role of the ceRNA-based LINC01122/TPD52 axis in the progression of PCa and its correlation with prognosis.

Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear. Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated. MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues − 503 to − 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models. MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.

CRPC remains a significant challenge in prostate cancer research. We aimed to elucidate the role of gut microbiota and its specific mechanisms in CRPC using a multidisciplinary approach. We analyzed 16S rRNA sequencing data from mouse fecal samples, revealing substantial differences in gut microbiota composition between CRPC and castration-sensitive prostate cancer mice, particularly in Firmicutes and Bacteroidetes. Functional analysis suggested different bacteria may influence CRPC via the α-linolenic acid metabolism pathway. In vivo, experiments utilizing mouse models and fecal microbiota transplantation (FMT) demonstrated that FMT from healthy control mice could decelerate tumor growth in CRPC mice, reduce TNF-α levels, and inhibit the activation of the TLR4/MyD88/NF-κB signaling pathway. Transcriptome sequencing identified crucial genes and pathways, with rescue experiments confirming the gut microbiota’s role in modulating CRPC progression through the TLR4/MyD88/NF-κB pathway. The activation of this pathway by TNF-α has been corroborated by in vitro cell experiments, indicating its role in promoting prostate cancer cell proliferation, migration, and invasion while inhibiting apoptosis. Gut microbiota dysbiosis may promote CRPC development through TNF-α activation of the TLR4/MyD88/NF-κB signaling pathway, potentially linked to α-linolenic acid metabolism.

Androgen receptors (ARs) play key roles in prostate cancer (PCa) progression and castration-resistant prostate cancer (CRPC) resistance to drug therapy. SET and MYND domain containing protein 2 (SMYD2), a lysine methyltransferase, has been reported to promote tumors by transcriptionally methylating important oncogenes or tumor repressor genes. However, the role of SMYD2 in CRPC drug resistance remains unclear. In this study, we found that SMYD2 expression was significantly upregulated in PCa tissues and cell lines. High SMYD2 expression indicated poor CRPC-free survival and overall survival in patients. SMYD2 knockdown dramatically inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) potential of 22Rv1 and C4-2 cells. Conversely, ectopic overexpression of SMYD2 promoted these effects in 22Rv1 and C4-2 cells. Mechanistically, SMYD2 methylated and phosphorylated ARs to affect AR ubiquitination and proteasome degradation, which further alters the AR transcriptome in CRPC cells. Importantly, the SMYD2 inhibitor AZ505 had a synergistic therapeutic effect with enzalutamide in CRPC cells and mouse models; however, it could also re-sensitize resistant CRPC cells to enzalutamide. Our findings demonstrated that SMYD2 enhances the methylation and phosphorylation of ARs and affects AR ubiquitination and proteasome degradation to modulate CRPC cell resistance to enzalutamide, indicating that SMYD2 serves as a crucial oncogene in PCa and is an ideal therapeutic target for CRPC.

Tripartite motif-containing protein 28 (TRIM28), as a transcriptional cofactor, has pleiotropic biological effects, such as silencing genes, promoting cellular proliferation and differentiation, and facilitating DNA repair. It is reported that TRIM28 is also correlated with immune infiltration in liver cancer that highlights an unnoticed function of TRIM28 in immune system. However, the prognostic and immunotherapeutic role of TRIM28 in human cancer has not been elucidated. In this study, we conducted a systematic pan-cancer analysis and partial experimental validation of TRIM28 as an immunological and prognostic predictor and its involvement in immunotherapy resistance. We found that TRIM28 expression was higher in various tumor tissues than in normal tissues. Higher TRIM28 expression was associated with poorer prognosis in multiple cancers. The expression of TRIM28 was positively correlated with the presence of T cells, macrophages and neutrophils, and TRIM28 also promoted the infiltration of a series of immune cell. Moreover, TRIM28 affected a wide range of cancer-related scores, and the abnormal expression of TRIM28 was also involved in tumor mutational burden, drug sensitivity, and microsatellite instability in cancer. The results suggest that TRIM28 is a potentially valuable immune response indicator and a molecular biomarker for predicting the prognosis of cancer patients.