TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=85078086407&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14318-9
DO - 10.1038/s41467-020-14318-9
M3 - Article
C2 - 31974375
AN - SCOPUS:85078086407
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 441
ER -
