Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

Stanley Zhou, James R. Hawley, Fraser Soares, Giacomo Grillo, Mona Teng, Seyed Ali Madani Tonekaboni, Junjie Tony Hua, Ken J. Kron, Parisa Mazrooei, Musaddeque Ahmed, Christopher Arlidge, Hwa Young Yun, Julie Livingstone, Vincent Huang, Takafumi N. Yamaguchi, Shadrielle M.G. Espiritu, Yanyun Zhu, Tesa M. Severson, Alex Murison, Sarina CameronWilbert Zwart, Theodorus van der Kwast, Trevor J. Pugh, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Housheng Hansen He, Mathieu Lupien (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

51 Citations (Scopus)

Abstract

Prostate 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.

Original languageEnglish
Article number441
Number of pages13
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Jan 2020

Funding

We thank the Princess Margaret Genomics Centre and the Princess Margaret Bioin-formatics group for providing support and infrastructure for the computational analysis of this work as well as high-throughput sequencing support and the NKI Core Facility Molecular Pathology and Biobanking for technical support and providing tissue specimens. We thank all the members of the M.L. lab for their fruitful discussions and feedback. This work is supported Prostate Cancer Canada, Ontario Institute for Cancer Research funded by the Government of Ontario, The Princess Margaret Cancer Foundation (M.L. and R.G.B.), Movember Foundation (RS2014-04 to M.L. and RS2014-01 to P.C.B.), the Radiation Medicine Program Academic Enrichment Fund (R.G.B.), Terry Fox Research Institute New Investigator Award (P.C.B.), Canadian Institute of Health Research (CIHR) (FRN-153234 to M.L.), and New Investigator Award (P.C.B. and M.L.), Canadian Cancer Society Research Scientist Award (R.G.B.), Cancer Cancer Society Impact Award (P.C.B), the Dutch Cancer Society KWF/Alpe d’HuZes (10084 and NKI 2014-6711 ALPE to W.Z.), CIHR Graduate Scholarship—Master’s Research Award (J.R. H., M.T.). CIHR Graduate Scholarship—Doctoral Research Award (P.M., J.T.H.), Canadian Breast Cancer Foundation (CBCF) postdoctoral fellowship (K.J.K.), Investigator Award from the Ontario Institute for Cancer Research (M.L. and P.C.B.) and Movember Rising Star Award from Prostate Cancer Canada (M.L. and P.C.B.). W.Z. receives project funding from Astellas Pharma but the components of this manuscript provided by W.Z. and his team were funded by KWF Dutch Cancer Society and Oncode Institute. The other authors declare no competing interests.

FundersFunder number
KWF Dutch Cancer Society10084, NKI 2014-6711 ALPE

    Keywords

    • Binding Sites
    • Cell Line, Tumor
    • Cell Proliferation/genetics
    • Gene Expression Regulation, Neoplastic
    • Hepatocyte Nuclear Factor 3-alpha/genetics
    • Humans
    • Male
    • Mutation
    • Prostatic Neoplasms/genetics
    • Regulatory Sequences, Nucleic Acid
    • Transcription Factors/metabolism

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