No abstract

Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.

Background: Bladder cancer (BCa) is a prevalent urologic malignancy that shows a poor prognosis. Abnormal metabolism and its key genes play a critical role in BCa progression. In this study, the role played by PhosphoGlycerol Dehydrogenase (PHGDH), an important molecule of serine metabolism, was investigated with regard to the regulation of ferroptosis in BCa. Methods: The BCa tissues of 90 patients were analyzed by RNA-sequencing for differential pathways and genes. Western blot, qPCR, and IHC were used to determine PHGDH expression in the cell lines ( in vitro ) and patient tissues ( in vivo ). R software was used to analyze PHGDH expression, prognosis, and PHGDH+SLC7A11 score. The biological functions of PHGDH were examined through organoids, and in vitro and in vivo experiments. C11 probes, electron microscopy, and ferroptosis inhibitors/ inducers were used to detect cellular ferroptosis levels. Protein profiling, co-IP, and RIP assays were used to screen proteins that might bind to PHGDH. PHGDH-targeted inhibitor NCT-502 was used to evaluate its effect on BCa cells. Results: PHGDH was highly expressed in patients with BCa. Knock-down of PHGDH promoted ferroptosis, while the decreased proliferation of BCa cells. Additionally, PHGDH knock-down downregulated the expression of SLC7A11. Co-IP and mass spectrometry experiments indicate that PHGDH binds to PCBP2, an RNA-binding protein, and inhibits its ubiquitination degradation. PCBP2 in turn stabilizes SLC7A11 mRNA and increases its expression. NCT-502, a PHGDH inhibitor, promotes ferroptosis and inhibits tumor progression in BCa. The PHGDH+ SLC7A11 score was significantly correlated with patient prognosis. Conclusions: To conclude, the PHGDH, via interaction with PCBP2, upregulates SLC7A11 expression. This inhibits ferroptosis and promotes the malignant progression of BCA. The results of this study indicated that NCT-502 could serve as a therapeutic strategy for BCa.

The genus Malassezia is important in the aetiology of facial seborrhoeic dermatitis (FSD), which is the most common clinical type. The purpose of this study was to analyse the distribution of Malassezia species in the facial lesions of Chinese seborrhoeic dermatitis (SD) patients and healthy individuals. Sixty-four isolates of Malassezia were isolated from FSD patients and 60 isolates from healthy individuals. Sequence analysis of the internal transcribed spacer (ITS) region was used to identify the isolates. The most frequently identified Malassezia species associated with FSD was M. furfur (76.56%), followed by M. sympodialis (12.50%) and M. japonica (9.38%). The most frequently isolated species in healthy individuals were M. furfur (61.67%), followed by M. sympodialis (25.00%), M. japonica (6.67%), M. globosa (3.33%), and M. obtusa (3.33%). Overall, our study revealed that while M. furfur is the predominant Malassezia species in Chinese SD patients, there is no significant difference in the distribution of Malassezia species between Chinese SD patients and healthy individuals.

BackgroundTobacco smoking is a carcinogen for many cancers including bladder cancer. The microbiota is involved in the occurrence, development, and treatment of tumors. We explored the composition of male urinary microbiome and the correlation between tobacco smoking and microbiome in this study.MethodsAlpha diversity, principal component analysis (PCA) and Adonis analysis, linear discriminant analysis (LDA) coupled with effect size measurement, and PICRUSt function predictive analysis were used to compare different microbiome between smokers and non-smokers in men.ResultsThere were 26 qualified samples included in the study. Eleven of them are healthy controls, and the others are from men with bladder cancer. Simpson index and the result of PCA analysis between smokers and non-smokers were not different (P > 0.05) in healthy men. However, the abundance of Bacteroidaceae, Erysipelotrichales, Lachnospiraceae, Bacteroides, and so on in the urinary tract of smokers is much higher than that of non-smokers. Compared to non-smokers, the alpha diversity in smokers was elevated in patients with bladder cancer (P < 0.05). PCA analysis showed a significant difference between smokers and non-smokers (P < 0.001), indicating that tobacco smoking plays a vital role in urinary tract microbial composition.ConclusionThe composition of microbiome in the urinary tract is closely related to tobacco smoking. This phenomenon is more significant in patients with bladder cancer. This indicates tobacco smoking may promote the occurrence and development of bladder cancer by changing urinary tract microbiome.