Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer
Madani, Tonekaboni SA
Van der Kwast, T
Bristow, Robert G
AffiliationPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
MetadataShow full item record
AbstractProstate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.
CitationZhou S, Hawley JR, Soares F, Grillo G, Teng M, Madani Tonekaboni SA, et al. Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer. Nat Commun. 2020;11(1):441.
- Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer.
- Authors: Parolia A, Cieslik M, Chu SC, Xiao L, Ouchi T, Zhang Y, Wang X, Vats P, Cao X, Pitchiaya S, Su F, Wang R, Feng FY, Wu YM, Lonigro RJ, Robinson DR, Chinnaiyan AM
- Issue date: 2019 Jul
- Androgen receptor-independent function of FoxA1 in prostate cancer metastasis.
- Authors: Jin HJ, Zhao JC, Ogden I, Bergan RC, Yu J
- Issue date: 2013 Jun 15
- FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.
- Authors: Jones D, Wade M, Nakjang S, Chaytor L, Grey J, Robson CN, Gaughan L
- Issue date: 2015 Oct 6
- Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors.
- Authors: Mazrooei P, Kron KJ, Zhu Y, Zhou S, Grillo G, Mehdi T, Ahmed M, Severson TM, Guilhamon P, Armstrong NS, Huang V, Yamaguchi TN, Fraser M, van der Kwast T, Boutros PC, He HH, Bergman AM, Bristow RG, Zwart W, Lupien M
- Issue date: 2019 Dec 9
- FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation, and migration in prostate cancer cells.
- Authors: Guo W, Keener AL, Jing Y, Cai L, Ai J, Zhang J, Fisher AL, Fu G, Wang Z
- Issue date: 2015 Jun 15