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Published on: April 5, 2024
KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B
Yin Sun1, Ying Tsai1, Ronald Wood2
1Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
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.
Insights
Single-nucleotide polymorphisms (SNPs) in KDM3B influence radiation therapy toxicity in prostate cancer patients. Lower KDM3B expression, linked to urinary frequency, results from SNP-regulated noncoding RNA, causing tissue inflammation.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Radiation Oncology
Background:
- Genome-wide association studies (GWAS) have linked specific single-nucleotide polymorphisms (SNPs) to radiation therapy (RT) toxicities in prostate cancer patients.
- SNP rs17599026 in KDM3B is associated with increased late urinary frequency after RT.
Purpose of the Study:
- To elucidate the mechanistic link between KDM3B SNP rs17599026 and radiation-induced urinary toxicity.
- To investigate how KDM3B expression is modulated by genetic variants and its role in radiation response.
Main Methods:
- Analysis of KDM3B protein expression and SNP allele variants in human tissues and cell lines.
- Investigation of KDM3B's role in radiation toxicity using a murine model with heterozygous Kdm3b deletion.
- Assessment of molecular and physiological markers of inflammation and urinary function.
Main Results:
- SNP rs17599026 is located in a critical motif for circular RNA expression, affecting microRNA sponging and KDM3B regulation.
- Reduced KDM3B expression in mice correlated with altered urination patterns post-bladder irradiation.
- Tissue inflammation, assessed via gene expression, lymphocyte infiltration, and ultrasound, was linked to lower KDM3B levels.
Conclusions:
- KDM3B SNPs modulate gene expression via noncoding RNAs, impacting KDM3B protein levels.
- Differential KDM3B expression contributes to radiation toxicity through molecular and physiological tissue inflammation.
- Findings provide a basis for developing targeted strategies to mitigate RT toxicity in prostate cancer survivors.
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