International journal of radiation oncology, biology, physics · 2025
KDM3B Regulates Postradiation Fibrotic Responses in Prostate Stroma via N6-methyladenosine Modification of LOX.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Dong Antao, Sun Xin, Chen Lei, Tsai Ying, Kerns Sarah, Marples Brian, Xing Defu, Chen Yuhchyau, Xie Dongdong, Sun Yin
Аннотация
PURPOSE: Genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) linked to radiation therapy (RT)-induced toxicities in patients with prostate cancer. SNP rs17599026, located in intron 21 of the KDM3B gene, has been associated with late-onset urinary toxicity, with an increased frequency of urination observed 2 years post-RT compared with pretreatment conditions. This study aimed to explore the underlying mechanisms driving this association.
METHODS AND MATERIALS: A clustered regularly interspaced short palindromic repeats-dead Cas9 prime editing system was used to mimic KDM3B genetic variants in prostate stromal cell lines. Murine models with wild-type and heterozygous Kdm3b genotypes were used to assess fibrosis following radiation. RNA immunoprecipitation, transcript stability assays, and protein analysis elucidated the role of N6-methyladenosine (m6A) modification in regulating lysyl oxidase (LOX) expression. α-ketoglutarate (α-KG) supplementation was tested for its effects on KDM3B protein stability, LOX expression, and fibrosis mitigation.
RESULTS: The rs17599026 SNP reduced KDM3B protein expression via circular RNA and microRNA-mediated mechanisms, leading to decreased m6A modification and increased stability of LOX messenger RNA. Elevated LOX expression promoted collagen cross-linking and fibrosis in prostate stroma. α-KG supplementation restored KDM3B protein levels, reduced LOX expression, and mitigated fibrosis in vitro and in vivo.
CONCLUSIONS: KDM3B genetic variations influence radiation-induced fibrosis through posttranscriptional regulation of LOX. Dietary α-KG supplementation may serve as a mechanism-based strategy to alleviate radiation toxicity in patients with prostate cancer, offering a potential therapeutic pathway to improve treatment outcomes.
METHODS AND MATERIALS: A clustered regularly interspaced short palindromic repeats-dead Cas9 prime editing system was used to mimic KDM3B genetic variants in prostate stromal cell lines. Murine models with wild-type and heterozygous Kdm3b genotypes were used to assess fibrosis following radiation. RNA immunoprecipitation, transcript stability assays, and protein analysis elucidated the role of N6-methyladenosine (m6A) modification in regulating lysyl oxidase (LOX) expression. α-ketoglutarate (α-KG) supplementation was tested for its effects on KDM3B protein stability, LOX expression, and fibrosis mitigation.
RESULTS: The rs17599026 SNP reduced KDM3B protein expression via circular RNA and microRNA-mediated mechanisms, leading to decreased m6A modification and increased stability of LOX messenger RNA. Elevated LOX expression promoted collagen cross-linking and fibrosis in prostate stroma. α-KG supplementation restored KDM3B protein levels, reduced LOX expression, and mitigated fibrosis in vitro and in vivo.
CONCLUSIONS: KDM3B genetic variations influence radiation-induced fibrosis through posttranscriptional regulation of LOX. Dietary α-KG supplementation may serve as a mechanism-based strategy to alleviate radiation toxicity in patients with prostate cancer, offering a potential therapeutic pathway to improve treatment outcomes.