Gut microbiota modulation of epigenetic target EHMT2: Lacticaseibacillus rhamnosus Fb7-311 regulated renal cell carcinoma apoptosis and metastasis

Abstract Renal cell carcinoma (RCC), also known as renal cell cancer or renal cell adenocarcinoma, is the most common type of kidney cancer and a common malignant tumor of the urinary system. Although surgical interventions and cancer treatments such as chemotherapy are commonly used to treat RCC, the persistently low 5-year survival rate and high relapse rate underscore the continued need to identify novel therapeutic targets for the development of new RCC treatments. Here, in this study, we therefore identified EHMT2 overexpression using RCC RNA-sequencing data derived from The Cancer Genome Atlas database. EHMT2 knockdown induced apoptosis and inhibited the migration/invasion of the A498 and Caki-1 RCC cell lines. Treatment with BIX-01294, an EHMT2-specific inhibitor, similarly suppressed growth and inhibited the migration/invasion of RCC cell lines, confirming the functional role of EHMT2 in RCC progression. Furthermore, DDIT3 was identified as a direct downstream target of EHMT2 and its expression was upregulated following EHMT2 downregulation by epigenetic regulation. Moreover, 3D spheroid models and in vivo experiments supported the therapeutic potential of EHMT2 as a therapeutic target for RCC treatment. In addition, by screening the components of the gut microbiota capable of modulating the EHMT2–DDIT3 axis, we identified Lacticaseibacillus rhamnosus Fb7-311, whose culture supernatant promoted apoptosis through regulation of the EHMT2–DDIT3 pathway. Thus, the development of EHMT2-specific inhibitors and the therapeutic application of L. rhamnosus Fb7-311 may represent promising strategies for effective treatment and clinical guidance of RCC treatment.