Cellular heterogeneity of PCa contributes to hormonal therapy failure, but CXCR2 on neuroendocrine cells is a potential therapeutic target.

Significance: We report that androgen receptor (AR) promotes glutaminase 1 (GLS1) expression and glutamine utilization to support the survival of prostate cancer (PCa) cells. Hormonal therapy inhibits AR and decreases GLS1 expression and glutamine utilization to achieve therapeutic effect. Our results suggest that eventually the tumor cells switch GLS1 expression from the AR-dependent KGA isoform to the androgen-independent and enzymatically more potent GAC isoform, which increases glutamine utilization and can contribute to the development of castration-resistant PCa. Our work has discovered a previously unknown AR function, a metabolic mechanism of hormonal therapy and an important therapeutic target more specific than AR. Targeting GLS1 may achieve similar therapeutic efficacy but without the side effects resulting from inhibiting AR’s other important physiologic functions.

Nowadays, human microbiome research is rapidly growing and emerging evidence has witnessed the critical role that oral microbiome plays in the process of human health and disease. Oral microbial dysbiosis has been confirmed as a contributory cause for diseases in multiple body systems, ranging from the oral cavity to the gastrointestinal, endocrine, immune, cardiovascular, and even nervous system. As research progressing, oral microbiome‐based diagnosis and therapy are proposed and applied, which may represent potential drug targets in systemic diseases. Recent studies have uncovered the possible association between periodontal disease and prostatic disease, suggesting new prevention and therapeutic treatment for the disease by targeting periodontal pathogens. Thus, we performed this review to first explore the association between the oral microbiome and prostatic disease, according to current knowledge based on published articles, and then mainly focus on the underlying molecular and cellular mechanisms and the potential prevention and treatment derived from these mechanistic studies.

Periodontitis has been proposed as a novel risk factor of genitourinary cancers: although periodontitis and genitourinary cancers are two totally distinct types of disorders, epidemiological and clinical studies, have established associations between them. Dysbiosis of oral microbiota has already been established as a major factor contributing to periodontitis. Recent emerging epidemiological evidence and the detection of oral microbiota in genitourinary organs indicate the presence of an oral-genitourinary axis and oral microbiota may be involved in the pathogenesis of genitourinary cancers. Therefore, oral microbiota provides the bridge between periodontitis and genitourinary cancers. We have carried out this narrative review which summarizes epidemiological studies exploring the association between periodontitis and genitourinary cancers. We have also highlighted the current evidence demonstrating the capacity of oral microbiota to regulate almost all hallmarks of cancer, and proposed the potential mechanisms of oral microbiota in the development of genitourinary cancers.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m⁶A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m⁶A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.