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Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer
Zhou, S Hawley, JR Soares, F Grillo, G Teng, M Madani, Tonekaboni SA Hua, JT Kron, KJ Mazrooei, P Ahmed, M
Zhou, S
Hawley, JR
Soares, F
Grillo, G
Teng, M
Madani, Tonekaboni SA
Hua, JT
Kron, KJ
Mazrooei, P
Ahmed, M
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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.
Authors
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, Robert G
He, HH
Lupien, M
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, Robert G
He, HH
Lupien, M
Description
Date
2020
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Article
Citation
Zhou 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.