KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses

Purpose Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with radiotherapy (RT) toxicities in prostate cancer patients. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency two years after RT compared with pre-treatment conditions. The present study aimed to provide mechanistic insights for this association. Methods and Materials Using human tissues and cell lines, we examined the protein expression of KDM3B and molecular mechanisms underlying the SNP modulation by variants of KDM3B SNP alleles. In animals with normal and heterozygous expressions of Kdm3b, we examined the relationship between Kdm3b expression and radiation toxicity. Results KDM3B rs17599026 lies in a motif important for circular RNA expression which is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of Kdm3b gene, we found that lower Kdm3b expression is associated with altered pattern of urination after bladder irradiation, which is related to differential degrees of tissue inflammation as measured by analyses of gene expression, lymphocyte infiltration, and non-invasive ultrasound imaging. Conclusions KDM3B SNPs can impact its expression through regulating noncoding (nc) RNA expression. Differential KDM3B expression underlies radiation toxicity through tissue inflammation at the molecular and physiological level. Our study outcome offers a foundation for mechanism-based mitigation for radiation toxicity for prostate cancer survivors.