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KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses. Int J Radiat Oncol Biol Phys 2024 May 01;119(1):251-260

Date

11/27/2023

Pubmed ID

38008196

DOI

10.1016/j.ijrobp.2023.11.033

Scopus ID

2-s2.0-85180584261 (requires institutional sign-in at Scopus site)

Abstract

PURPOSE: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with radiation therapy (RT) toxicities in patients with prostate cancer. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency 2 years after RT compared with pretreatment 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 that is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of the 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 noninvasive ultrasound imaging.

CONCLUSIONS: KDM3B SNPs can impact its expression through regulating noncoding 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.

Author List

Sun Y, Tsai Y, Wood R, Shen B, Chen J, Zhou Z, Zeng G, Marples B, Kerns S, Chen Y

Author

Sarah L. Kerns PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Genome-Wide Association Study
Humans
Inflammation
Jumonji Domain-Containing Histone Demethylases
Male
Mice
Polymorphism, Single Nucleotide
Prostatic Neoplasms