Epigenetic dysregulation contributes to bladder cancer tumorigenesis. H3K36me2 demethylase KDM2A functions as an important epigenetic regulator of cell fate in many types of tumors. However, its role in bladder cancer remains unknown. Here, we revealed a positive correlation between KDM2A gene copy number gain and upregulation of KDM2A mRNA expression in bladder cancer. Moreover, a super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder cancer, resulting in a significantly higher expression of KDM2A mRNA compared to that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the proliferation, invasion, and spheroid formation of high-grade bladder cancer cells and inhibited tumor growth in mouse xenograft models. Furthermore, we identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant phenotypes of high-grade bladder cancer cells. The combination of the KDM2A inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) synergistically inhibited the proliferation of high-grade bladder cancer cells, suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for the treatment of high-grade bladder cancer.

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Clostridium tyrobutyricum shows probiotic properties and can affect the composition of gut microbiota and regulate the intestinal immune system. Compared with other probiotics, this spore-producing bacterium shows unparalleled advantages in commercial production. In addition to being resistant to extreme living environments for extended periods, its endophytic spores are implicated in inhibiting cancer cell growth. We speculated that C. tyrobutyricum spores can also promote gut health, which mean it can maintain intestinal homeostasis. To date, the beneficial effects of C. tyrobutyricum spores on gut health have not been reported. In this study, a Spo0A-overexpressing C. tyrobutyricum strain was developed to increase spore production, and its probiotic effects on the gut were assessed. Compared with the wild-type, the engineered strain showed significantly increased sporulation rates. Mice administered with the engineered strain exhibited enhanced intestinal villi and the villus height/crypt depth ratio, weight gain and improved Firmicutes/Bacteroidetes ratio to facilitate intestinal homeostasis. This study demonstrated for the first time that enhanced spore production in C. tyrobutyricum can improve intestinal homeostasis, which is advantageous for its commercial application in food and pharmaceutical industry.