4.6
CiteScore
2.2
Impact Factor
- ISSN 1674-8301
- CN 32-1810/R
4.6
2.2
| Citation: |
Lulu Fan, Hao Wang, Shuai Ben, Yifei Cheng, Silu Chen, Zhutao Ding, Lingyan Zhao, Shuwei Li, Meilin Wang, Gong Cheng. Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression[J]. The Journal of Biomedical Research, 2024, 38(2): 149-162. DOI: 10.7555/JBR.37.20230049
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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.
This work received no funding from any source.
We are grateful to all the people who helped us accomplish this project.
CLC number: R737.25, Document code: A
The authors reported no conflict of interests.
| [1] |
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209–249. doi: 10.3322/caac.21660
|
| [2] |
Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer[J]. Pharmacol Ther, 2013, 140(3): 223–238. doi: 10.1016/j.pharmthera.2013.07.003
|
| [3] |
Pernar CH, Ebot EM, Wilson KM, et al. The epidemiology of prostate cancer[J]. Cold Spring Harb Perspect Med, 2018, 8(12): a030361. doi: 10.1101/cshperspect.a030361
|
| [4] |
Tian P, Zhong M, Wei G. Mechanistic insights into genetic susceptibility to prostate cancer[J]. Cancer Lett, 2021, 522: 155–163. doi: 10.1016/j.canlet.2021.09.025
|
| [5] |
Hnisz D, Abraham BJ, Lee TI, et al. Super-enhancers in the control of cell identity and disease[J]. Cell, 2013, 155(4): 934–947. doi: 10.1016/j.cell.2013.09.053
|
| [6] |
Tippens ND, Vihervaara A, Lis JT. Enhancer transcription: what, where, when, and why?[J]. Genes Dev, 2018, 32(1): 1–3. doi: 10.1101/gad.311605.118
|
| [7] |
Lovén J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers[J]. Cell, 2013, 153(2): 320–334. doi: 10.1016/j.cell.2013.03.036
|
| [8] |
Chen X, Ma Q, Shang Z, et al. Super-enhancer in prostate cancer: transcriptional disorders and therapeutic targets[J]. NPJ Precis Oncol, 2020, 4(1): 31. doi: 10.1038/s41698-020-00137-0
|
| [9] |
Kandaswamy R, Sava GP, Speedy HE, et al. Genetic predisposition to chronic lymphocytic leukemia is mediated by a BMF super-enhancer polymorphism[J]. Cell Rep, 2016, 16(8): 2061–2067. doi: 10.1016/j.celrep.2016.07.053
|
| [10] |
Zhang X, Wang Y, Chiang HC, et al. BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells[J]. Breast Cancer Res, 2019, 21(1): 51. doi: 10.1186/s13058-019-1132-1
|
| [11] |
Awada Z, Nasr R, Akika R, et al. DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer[J]. Clin Epigenetics, 2019, 11(1): 138. doi: 10.1186/s13148-019-0725-y
|
| [12] |
Cella M, Colonna M. Aryl hydrocarbon receptor: linking environment to immunity[J]. Semin Immunol, 2015, 27(5): 310–314. doi: 10.1016/j.smim.2015.10.002
|
| [13] |
Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe[J]. Nat Rev Cancer, 2014, 14(12): 801–814. doi: 10.1038/nrc3846
|
| [14] |
Shimizu Y, Nakatsuru Y, Ichinose M, et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor[J]. Proc Natl Acad Sci U S A, 2000, 97(2): 779–782. doi: 10.1073/pnas.97.2.779
|
| [15] |
Tabatabaei SM, Heyworth JS, Knuiman MW, et al. Dietary benzo[a]pyrene intake from meat and the risk of colorectal cancer[J]. Cancer Epidemiol Biomarkers Prev, 2010, 19(12): 3182–3184. doi: 10.1158/1055-9965.EPI-10-1051
|
| [16] |
Amadou A, Praud D, Coudon T, et al. Risk of breast cancer associated with long-term exposure to benzo[a]pyrene (BaP) air pollution: evidence from the French E3N cohort study[J]. Environ Int, 2021, 149: 106399. doi: 10.1016/j.envint.2021.106399
|
| [17] |
Hrubá E, Vondráček J, Líbalová H, et al. Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands[J]. Toxicol Lett, 2011, 206(2): 178–188. doi: 10.1016/j.toxlet.2011.07.011
|
| [18] |
Gohagan JK, Prorok PC, Greenwald P, et al. The PLCO cancer screening trial: background, goals, organization, operations, results[J]. Rev Recent Clin Trials, 2015, 10(3): 173–180. doi: 10.2174/1574887110666150730123004
|
| [19] |
Yeager M, Orr N, Hayes RB, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24[J]. Nat Genet, 2007, 39(5): 645–649. doi: 10.1038/ng2022
|
| [20] |
Tryka KA, Hao L, Sturcke A, et al. NCBI's database of genotypes and phenotypes: dbGaP[J]. Nucleic Acids Res, 2014, 42(D1): D975–D979. doi: 10.1093/nar/gkt1211
|
| [21] |
Zhang Y, Huang Y, Wang D, et al. LncRNA DSCAM-AS1 interacts with YBX1 to promote cancer progression by forming a positive feedback loop that activates FOXA1 transcription network[J]. Theranostics, 2020, 10(23): 10823–10837. doi: 10.7150/thno.47830
|
| [22] |
Nguyen DT, Yang W, Renganathan A, et al. Acetylated HOXB13 regulated super enhancer genes define therapeutic vulnerabilities of castration-resistant prostate cancer[J]. Clin Cancer Res, 2022, 28(18): 4131–4145. doi: 10.1158/1078-0432.CCR-21-3603
|
| [23] |
Islami F, Moreira DM, Boffetta P, et al. A systematic review and meta-analysis of tobacco use and prostate cancer mortality and incidence in prospective cohort studies[J]. Eur Urol, 2014, 66(6): 1054–1064. doi: 10.1016/j.eururo.2014.08.059
|
| [24] |
Wilson SR, Joshi AD, Elferink CJ. The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner[J]. J Pharmacol Exp Ther, 2013, 345(3): 419–429. doi: 10.1124/jpet.113.203786
|
| [25] |
Shan J, Al-Rumaihi K, Rabah D, et al. Genome scan study of prostate cancer in Arabs: identification of three genomic regions with multiple prostate cancer susceptibility loci in Tunisians[J]. J Transl Med, 2013, 11: 121. doi: 10.1186/1479-5876-11-121
|
| [26] |
Qiu X, Boufaied N, Hallal T, et al. MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets[J]. Nat Commun, 2022, 13(1): 2559. doi: 10.1038/s41467-022-30257-z
|
| [27] |
Xu K, Wu Z, Groner AC, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent[J]. Science, 2012, 338(6113): 1465–1469. doi: 10.1126/science.1227604
|
| [28] |
Flaveny CA, Murray IA, Chiaro CR, et al. Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice[J]. Mol Pharmacol, 2009, 75(6): 1412–1420. doi: 10.1124/mol.109.054825
|
| [29] |
Gutiérrez-Vázquez C, Quintana FJ. Regulation of the immune response by the aryl hydrocarbon receptor[J]. Immunity, 2018, 48(1): 19–33. doi: 10.1016/j.immuni.2017.12.012
|
| [30] |
Barul C, Parent ME. Occupational exposure to polycyclic aromatic hydrocarbons and risk of prostate cancer[J]. Environ Health, 2021, 20(1): 71. doi: 10.1186/s12940-021-00751-w
|
| [31] |
Gao M, Li H, Dang F, et al. Induction of proliferative and mutagenic activity by benzo(a)pyrene in PC-3 cells via JAK2/STAT3 pathway[J]. Mutat Res, 2020, 821: 111720. doi: 10.1016/j.mrfmmm.2020.111720
|
| [32] |
Fabiani R, Minelli L, Bertarelli G, et al. A western dietary pattern increases prostate cancer risk: a systematic review and meta-analysis[J]. Nutrients, 2016, 8(10): 626. doi: 10.3390/nu8100626
|
| [33] |
Di Maso M, Augustin LSA, Toffolutti F, et al. Adherence to mediterranean diet, physical activity and survival after prostate cancer diagnosis[J]. Nutrients, 2021, 13(1): 243. doi: 10.3390/nu13010243
|
| [34] |
Ferro M, Lucarelli G, Buonerba C, et al. Narrative review of Mediterranean diet in Cilento: longevity and potential prevention for prostate cancer[J]. Ther Adv Urol, 2021, 13: 17562872211026404. doi: 10.1177/17562872211026404
|
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