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 Cameron; Wilbert Zwart; Theodorus van der Kwast; Trevor J. Pugh; Michael Fraser; Paul C. Boutros; Robert G. Bristow; Housheng Hansen He; Mathieu Lupien

doi:10.1038/s41467-020-14318-9

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)

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Article number	441
Number of pages	13
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14318-9
Publication status	Published - 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.

Funders	Funder number
KWF Dutch Cancer Society	10084, 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-14318-9

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Zhou, S., Hawley, J. R., Soares, F., Grillo, G., Teng, M., Madani Tonekaboni, S. A., Hua, J. T., Kron, K. J., Mazrooei, P., Ahmed, M., Arlidge, C., Yun, H. Y., Livingstone, J., Huang, V., Yamaguchi, T. N., Espiritu, S. M. G., Zhu, Y., Severson, T. M., Murison, A., ... Lupien, M. (2020). Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer. Nature Communications, 11(1), Article 441. https://doi.org/10.1038/s41467-020-14318-9

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title = "Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer",

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.",

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Zhou, S, Hawley, JR, Soares, F, Grillo, G, Teng, M, Madani Tonekaboni, SA, Hua, JT, Kron, KJ, Mazrooei, P, Ahmed, M, Arlidge, C, Yun, HY, Livingstone, J, Huang, V, Yamaguchi, TN, Espiritu, SMG, Zhu, Y, Severson, TM, Murison, A, Cameron, S, Zwart, W, van der Kwast, T, Pugh, TJ, Fraser, M, Boutros, PC, Bristow, RG, He, HH & Lupien, M 2020, 'Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer', Nature Communications, vol. 11, no. 1, 441. https://doi.org/10.1038/s41467-020-14318-9

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T1 - Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

AU - Zhou, Stanley

AU - Hawley, James R.

AU - Soares, Fraser

AU - Grillo, Giacomo

AU - Teng, Mona

AU - Madani Tonekaboni, Seyed Ali

AU - Hua, Junjie Tony

AU - Kron, Ken J.

AU - Mazrooei, Parisa

AU - Ahmed, Musaddeque

AU - Arlidge, Christopher

AU - Yun, Hwa Young

AU - Livingstone, Julie

AU - Huang, Vincent

AU - Yamaguchi, Takafumi N.

AU - Espiritu, Shadrielle M.G.

AU - Zhu, Yanyun

AU - Severson, Tesa M.

AU - Murison, Alex

AU - Cameron, Sarina

AU - Zwart, Wilbert

AU - van der Kwast, Theodorus

AU - Pugh, Trevor J.

AU - Fraser, Michael

AU - Boutros, Paul C.

AU - Bristow, Robert G.

AU - He, Housheng Hansen

AU - Lupien, Mathieu

PY - 2020/1/23

Y1 - 2020/1/23

N2 - 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.

AB - 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.

KW - Binding Sites

KW - Cell Line, Tumor

KW - Cell Proliferation/genetics

KW - Gene Expression Regulation, Neoplastic

KW - Hepatocyte Nuclear Factor 3-alpha/genetics

KW - Humans

KW - Male

KW - Mutation

KW - Prostatic Neoplasms/genetics

KW - Regulatory Sequences, Nucleic Acid

KW - Transcription Factors/metabolism

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DO - 10.1038/s41467-020-14318-9

M3 - Article

C2 - 31974375

AN - SCOPUS:85078086407

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 441

ER -

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

Abstract

Funding

Keywords

UN SDGs

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