Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression
Lulu Fan1
Hao Wang1
Shuai Ben1
Yifei Cheng1
Silu Chen1
Zhutao Ding1
Lingyan Zhao1
Shuwei Li1
Meilin Wang1
Gong Cheng2
1.Department of Environmental Genomics,Jiangsu Key Laboratory of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Genetic Toxicology,the Key Laboratory of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China2.Department of Urology,the First Affiliated Hospital of Nanjing Medical University,Jiangsu Province Hospital,Nanjing,Jiangsu 210029,China
摘要：Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10-5).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r2=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.
机标关键词：expressionprostategeneticvariantcancerriskahr-mediatedbap-activated
分类号：R737.25(泌尿生殖器肿瘤)
论文发表日期：2024-03-30
在线出版日期：2026-03-31（本平台首次上网日期，不代表文献的发表时间）
页数：15( 中插3,149-162 )
英文信息