{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:39:20Z","timestamp":1792175960167,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,4]],"date-time":"2025-01-04T00:00:00Z","timestamp":1735948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vranos Family Foundation Career Development Award in Prostate Cancer from Mayo Clinic Center for Clinical and Translational Science (CCaTS)","award":["FP123048"],"award-info":[{"award-number":["FP123048"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>(1) Background: Prostate cancer treatment efficacy is significantly influenced by androgen receptor (AR) signaling pathways. SLC22A3, a membrane transporter, has been linked to SNP rs9364554 risk loci for drug efficacy in prostate cancer. (2) Methods: We examined the location of SNP rs9364554 in the genome and utilized TCGA and other publicly available datasets to analyze the association of this SNP with SLC22A3 transcription levels. We verified onco-mining findings in prostate cancer cell lines using quantitative PCR and Western blots. Additionally, we employed electrophoretic mobility shift assay (EMSA) to detect the binding affinity of transcription factors to this SNP. The ChIP-Seq was used to analyze the enrichment of H3K27ac on the SLC22A3 promoter. (3) Results: In this study, we revealed that SNP rs9364554 resides in the SLC22A3 gene and affects its transcription. The downregulation of SLC22A3 is associated with drug resistance. More importantly, we found that this SNP has different binding affinities with transcription factors, specifically FOXA1 and AR, which significantly affects their regulation of SLC22A3 transcription. (4) Conclusions: Our findings highlight the potential of using this SNP as a biomarker for predicting chemotherapeutic outcomes and uncover possible mechanisms underlying drug resistance in advanced prostate cancers. More importantly, it provides a clinical foundation for targeting FOXA1 to enhance drug efficacy in prostate cancer patients.<\/jats:p>","DOI":"10.3390\/biom15010064","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T09:17:02Z","timestamp":1736155022000},"page":"64","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SNP rs9364554 Modulates Androgen Receptor Binding and Drug Response in Prostate Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1646-7276","authenticated-orcid":false,"given":"Yuqian","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"},{"name":"Department of Neurosurgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Cancer Center, Zhejiang Provincial People\u2019s Hospital, Affiliated People\u2019s Hospital of Hangzhou Medical College, Hangzhou 310025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2072-4826","authenticated-orcid":false,"given":"Liguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA"},{"name":"Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.14740\/wjon1191","article-title":"Epidemiology of Prostate Cancer","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"288","DOI":"10.5534\/wjmh.180040","article-title":"Role of Androgen Receptor in Prostate Cancer: A Review","volume":"37","author":"Fujita","year":"2019","journal-title":"World J. Men\u2019s Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cell.2009.04.056","article-title":"Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer","volume":"138","author":"Wang","year":"2009","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41391-018-0079-0","article-title":"Androgen-targeted therapy in men with prostate cancer: Evolving practice and future considerations","volume":"22","author":"Crawford","year":"2019","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.1038\/onc.2013.206","article-title":"Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches","volume":"32","author":"Karantanos","year":"2013","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tewari, A.K., Yardimci, G.G., Shibata, Y., Sheffield, N.C., Song, L., Taylor, B.S., Georgiev, S.G., Coetzee, G.A., Ohler, U., and Furey, T.S. (2012). Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity. Genome Biol., 13.","DOI":"10.1186\/gb-2012-13-10-r88"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Miller, K.J., Henry, I., Maylin, Z., Smith, C., Arunachalam, E., Pandha, H., and Asim, M. (2023). A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1129140"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"614","DOI":"10.7150\/ijbs.8389","article-title":"Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer","volume":"10","author":"Zhao","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.molcel.2023.11.020","article-title":"FOXA1 forms biomolecular condensates that unpack condensed chromatin to function as a pioneer factor","volume":"84","author":"Ji","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41586-019-1347-4","article-title":"Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer","volume":"571","author":"Parolia","year":"2019","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3962","DOI":"10.1038\/emboj.2011.328","article-title":"Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer","volume":"30","author":"Sahu","year":"2011","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/nar\/gkad1126","article-title":"Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer","volume":"52","author":"Helminen","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/ng.2862","article-title":"A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding","volume":"46","author":"Huang","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s10038-007-0200-z","article-title":"SNPs in disease gene mapping, medicinal drug development and evolution","volume":"52","author":"Shastry","year":"2007","journal-title":"J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/j.juro.2013.12.030","article-title":"Prostate cancer risk alleles are associated with prostate cancer volume and prostate size","volume":"191","author":"Reinhardt","year":"2014","journal-title":"J. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1158\/2159-8290.CD-15-0315","article-title":"A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences","volume":"5","author":"Hoffmann","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41588-018-0142-8","article-title":"Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci","volume":"50","author":"Schumacher","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/ng.90","article-title":"Multiple newly identified loci associated with prostate cancer susceptibility","volume":"40","author":"Eeles","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mohelnikova-Duchonova, B., Strouhal, O., Hughes, D.J., Holcatova, I., Oliverius, M., Kala, Z., Campa, D., Rizzato, C., Canzian, F., and Pezzilli, R. (2017). SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. Sci. Rep., 7.","DOI":"10.1038\/srep43812"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1124\/dmd.121.000702","article-title":"Emerging Roles of the Human Solute Carrier 22 Family","volume":"50","author":"Yee","year":"2021","journal-title":"Drug Metab. Dispos."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/aje\/kww143","article-title":"Interactions Between Genome-Wide Significant Genetic Variants and Circulating Concentrations of 25-Hydroxyvitamin D in Relation to Prostate Cancer Risk in the National Cancer Institute BPC3","volume":"185","author":"Dimitrakopoulou","year":"2017","journal-title":"Am. J. Epidemiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/s41585-018-0077-y","article-title":"The role of ketoconazole in current prostate cancer care","volume":"15","author":"Patel","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e10659","DOI":"10.15252\/emmm.201910659","article-title":"The novel BET-CBP\/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer","volume":"11","author":"Yan","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","article-title":"Core transcriptional regulatory circuitry in human embryonic stem cells","volume":"122","author":"Boyer","year":"2005","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2102555","DOI":"10.1002\/advs.202102555","article-title":"Destruction of DNA-Binding Proteins by Programmable Oligonucleotide PROTAC (O\u2019PROTAC): Effective Targeting of LEF1 and ERG","volume":"8","author":"Shao","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/ncb2116","article-title":"Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2","volume":"12","author":"Chen","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_27","unstructured":"The Cancer Genome Atlas Research Network (2015). The Molecular Taxonomy of Primary Prostate Cancer. Cell, 163, 1011\u20131025."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.eururo.2017.08.027","article-title":"Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression","volume":"73","author":"Ren","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature11125","article-title":"The mutational landscape of lethal castration-resistant prostate cancer","volume":"487","author":"Grasso","year":"2012","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ccr.2010.05.026","article-title":"Integrative genomic profiling of human prostate cancer","volume":"18","author":"Taylor","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1056\/NEJMoa1903835","article-title":"Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer","volume":"381","author":"Davis","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nature13229","article-title":"Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer","volume":"510","author":"Asangani","year":"2014","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1038\/ng.3419","article-title":"The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis","volume":"47","author":"Pomerantz","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.cell.2004.11.022","article-title":"A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans","volume":"119","author":"Bond","year":"2004","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Osman, N., Shawky, A.E., and Brylinski, M. (2022). Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure. BMC Genom. Data, 23.","DOI":"10.1186\/s12863-021-01021-x"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.1158\/0008-5472.CAN-14-1030","article-title":"CtBP2 modulates the androgen receptor to promote prostate cancer progression","volume":"74","author":"Takayama","year":"2014","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3538","DOI":"10.1093\/nar\/gkr1219","article-title":"Genome-wide Runx2 occupancy in prostate cancer cells suggests a role in regulating secretion","volume":"40","author":"Little","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1093\/nar\/gku1375","article-title":"SUMO ligase PIAS1 functions as a target gene selective androgen receptor coregulator on prostate cancer cell chromatin","volume":"43","author":"Toropainen","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1038\/emboj.2012.112","article-title":"A transcriptional repressor co-regulatory network governing androgen response in prostate cancers","volume":"31","author":"Chng","year":"2012","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Shi, M., Hu, W., Estrella, H., Engebretsen, J., Nichols, T., Briere, D., Hosea, N., Los, G., and Rejto, P.A. (2012). Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding. BMC Genom., 13.","DOI":"10.1186\/1471-2164-13-355"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Toropainen, S., Niskanen, E.A., Malinen, M., Sutinen, P., Kaikkonen, M.U., and Palvimo, J.J. (2016). Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets. Sci. Rep., 6.","DOI":"10.1038\/srep33510"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6256","DOI":"10.1093\/nar\/gku281","article-title":"The ETS family member GABPalpha modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer","volume":"42","author":"Sharma","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.15252\/emmm.201505424","article-title":"Androgen receptor profiling predicts prostate cancer outcome","volume":"7","author":"Stelloo","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.1038\/onc.2015.496","article-title":"FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression","volume":"35","author":"Zhao","year":"2016","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1093\/nar\/gkt1382","article-title":"Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer","volume":"42","author":"Wu","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/nar\/gkw855","article-title":"Crosstalk between androgen and pro-inflammatory signaling remodels androgen receptor and NF-kappaB cistrome to reprogram the prostate cancer cell transcriptome","volume":"45","author":"Malinen","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1038\/emboj.2011.216","article-title":"Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1","volume":"30","author":"Robinson","year":"2011","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1038\/s41467-021-21860-7","article-title":"A noncanonical AR addiction drives enzalutamide resistance in prostate cancer","volume":"12","author":"He","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sung, M.K., Jang, J., Lee, K.S., Ghim, C.M., and Choi, J.K. (2016). Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans. Genome Biol., 17.","DOI":"10.1186\/s13059-016-1027-8"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Zhan, W., Cui, L., Yang, S., Zhang, K., Zhang, Y., and Yang, J. (2024). Natural variations of heterosis-related allele-specific expression genes in promoter regions lead to allele-specific expression in maize. BMC Genom., 25.","DOI":"10.1186\/s12864-024-10395-y"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1242\/dev.030403","article-title":"The function of non-coding RNAs in genomic imprinting","volume":"136","author":"Koerner","year":"2009","journal-title":"Development"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/75546","article-title":"The imprinted antisense RNA at the Igf2r locus overlaps but does not imprint Mas1","volume":"25","author":"Lyle","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Aurilio, G., Cimadamore, A., Mazzucchelli, R., Lopez-Beltran, A., Verri, E., Scarpelli, M., Massari, F., Cheng, L., Santoni, M., and Montironi, R. (2020). Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications. Cells, 9.","DOI":"10.3390\/cells9122653"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s11912-020-01003-9","article-title":"Clinical and Biological Features of Neuroendocrine Prostate Cancer","volume":"23","author":"Yamada","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1038\/s41586-019-1318-9","article-title":"FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes","volume":"571","author":"Adams","year":"2019","journal-title":"Nature"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/64\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:22:59Z","timestamp":1759918979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/64"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,4]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biom15010064"],"URL":"https:\/\/doi.org\/10.3390\/biom15010064","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,4]]}}}