Pioneer of prostate cancer: past, present and the future of FOXA1

Abstract

Prostate cancer is the most commonly diagnosed noncutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.

Keywords

FOXA1 / pioneer factor / transcription factor / prostate cancer / epigenetics

References

[1] Adams EJ, Karthaus WR, Hoover E, Liu D, Gruet A, Zhang Z, Cho H, DiLoreto R, Chhangawala S, Liu Y (2019) FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 571:408–412

[2] Ahmed M, Sallari RC, Guo H, Moore JH, He HH, Lupien M (2017) Variant Set Enrichment: an R package to identify diseaseassociated functional genomic regions. BioData Min 10:9

[3] American Cancer Society (2019) Cancer Facts & Figures 2019

[4] Annala M, Taavitsainen S, Vandekerkhove G, Bacon JVW, Beja K, Chi KN, Nykter M, Wyatt AW (2018)Frequent mutation of the FOXA1 untranslated region in prostate cancer. Commun Biol 1:122

[5] Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400

[6] Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat J-P, White TA, Stojanov P, Van Allen E, Stransky N (2012) Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 44:685–689

[7] Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BVSK, Varambally S (2016) Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 22:298–305

[8] Beltran H, Romanel A, Conteduca V, Casiraghi N, Sigouros M, Franceschini GM, Orlando F, Fedrizzi T, Ku S-Y, Dann E (2020) Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. J Clin Invest 130:1653–1668

[9] Cai C, He HH, Gao S, Chen S, Yu Z, Gao Y, Chen S, Chen MW, Zhang J, Ahmed M (2014) Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep 9:1618–1627

[10] Canadian Cancer Society (2019) Canadian Cancer Statistics 2019 Cancer Genome Atlas Research Network (2015) The Molecular Taxonomy of Primary Prostate Cancer. Cell 163:1011–1025

[11] Clark KL, Halay ED, Lai E, Burley SK (1993) Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364:412–420

[12] Dang CV, Reddy EP, Shokat KM, Soucek L (2017) Drugging the “undruggable” cancer targets. Nat Rev Cancer 17:502–508

[13] Dixon JR, Gorkin DU, Ren B (2016) Chromatin domains: the unit of chromosome organization. Mol Cell 62:668–680

[14] Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380

[15] Espiritu SMG, Liu LY, Rubanova Y, Bhandari V, Holgersen EM, Szyca LM, Fox NS, Chua MLK, Yamaguchi TN, Heisler LE (2018) The evolutionary landscape of localized prostate cancers drives clinical aggression. Cell 173:1003–1013.e15

[16] Fang Y, Liao G, Yu B (2019) LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol 12:129

[17] Farashi S, Kryza T, Clements J, Batra J (2019) Post-GWAS in prostate cancer: from genetic association to biological contribution. Nat Rev Cancer 19:46–59

[18] Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, Shiah Y-J, Yousif F, Lin X, Masella AP (2017) Genomic hallmarks of localized, non-indolent prostate cancer. Nature 541:359–364

[19] Gao N, Zhang J, Rao MA, Case TC, Mirosevich J, Wang Y, Jin R, Gupta A, Rennie PS, Matusik RJ (2003) The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol Endocrinol 17:1484–1507

[20] Gao S, Chen S, Han D, Barrett D, Han W, Ahmed M, Patalano S, Macoska JA, He HH, Cai C (2019) Forkhead domain mutations in FOXA1 drive prostate cancer progression. Cell Res 29:770–772

[21] Gao S, Chen S, Han D, Wang Z, Li M, Han W, Besschetnova A, Liu M, Zhou F, Barrett D (2020) Chromatin binding of FOXA1 is promoted by LSD1-mediated demethylation in prostate cancer. Nat Genet.

[22] Gerhardt J, Montani M, Wild P, Beer M, Huber F, Hermanns T, Müntener M, Kristiansen G (2012) FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer. Am J Pathol 180:848–861

[23] Grasso CS, Wu Y-M, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC (2012) The mutational landscape of lethal castration-resistant prostate cancer. Nature 487:239–243

[24] Grossfeld GD, Latini DM, Lubeck DP, Mehta SS, Carroll PR (2003) Predicting recurrence after radical prostatectomy for patients with high risk prostate cancer. J Urol 169:157–163

[25] Gui B, Gui F, Takai T, Feng C, Bai X, Fazli L, Dong X, Liu S, Zhang X, Zhang W (2019) Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function. Proceedings of the National Academy of Sciences 116:14573–14582

[26] Hankey W, Chen Z, Wang Q (2020) Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res.

[27] Hazelett DJ, Coetzee SG, Coetzee GA (2013) A rare variant, which destroys a FoxA1 site at 8q24, is associated with prostate cancer risk. Cell Cycle 12:379–380

[28] Huang FW, Mosquera JM, Garofalo A, Oh C, Baco M, Amin-Mansour A, Rabasha B, Bahl S, Mullane SA, Robinson BD (2017) Exome sequencing of African-American prostate cancer reveals loss-of-function ERF mutations. Cancer Discov 7:973–983

[29] Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T (2007) p53 is regulated by the lysine demethylase LSD1. Nature 449:105–108

[30] Iwafuchi M, Cuesta I, Donahue G, Takenaka N, Osipovich AB, Magnuson MA, Roder H, Seeholzer SH, Santisteban P, Zaret KS (2020) Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones. Nat Genet 52:418–427

[31] Jin H-J, Zhao JC, Ogden I, Bergan RC, Yu J (2013) Androgen receptor-independent function of FoxA1 in prostate cancer metastasis. Cancer Res 73:3725–3736

[32] Jin H-J, Zhao JC, Wu L, Kim J, Yu J (2014) Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program. Nat Commun 5:3972

[33] Kim J, Jin H, Zhao JC, Yang YA, Li Y, Yang X, Dong X, Yu J (2017) FOXA1 inhibits prostate cancer neuroendocrine differentiation. Oncogene 36:4072–4080

[34] Kohler S, Cirillo LA (2010) Stable chromatin binding prevents FoxA acetylation, preserving FoxA chromatin remodeling. J Biol Chem 285:464–472

[35] Li J, Xu C, Lee HJ, Ren S, Zi X, Zhang Z, Wang H, Yu Y, Yang C, Gao X (2020) A genomic and epigenomic atlas of prostate cancer in Asian populations. Nature 580:93–99

[36] Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132:958–970

[37] Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195

[38] Mazrooei P, Kron KJ, Zhu Y, Zhou S, Grillo G, Mehdi T, Ahmed M, Severson TM, Guilhamon P, Armstrong NS (2019) Cistrome partitioning reveals convergence of somatic mutations and risk variants on master transcription regulators in primary prostate tumors. Cancer Cell 36:674–689.e6

[39] Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AHFM, Günther T, Buettner R, Schüle R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptordependent transcription. Nature 437:436–439

[40] Müller S, Ackloo S, Arrowsmith CH, Bauser M, Baryza JL, Blagg J, Böttcher J, Bountra C, Brown PJ, Bunnage ME (2018) Science forum: donated chemical probes for open science. Elife 7:e34311

[41] Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, Piolot T, van Berkum NL, Meisig J, Sedat J (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485:381–385

[42] Parolia A, Cieslik M, Chu S-C, Xiao L, Ouchi T, Zhang Y, Wang X, Vats P, Cao X, Pitchiaya S (2019) Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature 571:413–418

[43] Pomerantz MM, Li F, Takeda DY, Lenci R, Chonkar A, Chabot M, Cejas P, Vazquez F, Cook J, Shivdasani RA (2015) The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet 47:1346–1351

[44] Pomerantz MM, Qiu X, Zhu Y, Takeda DY, Pan W, Baca SC, Gusev A, Korthauer KD, Severson TM, Ha G (2020) Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet 52:790–799

[45] Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, Foye A, Kothari V, Perry MD, Bailey AM (2018) Genomic hallmarks and structural variation in metastatic prostate cancer. Cell 174:758–769.e9

[46] Rotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang W-C, Huang F, Pan X, Yáñez A, Hazelett DJ (2018) ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med 24:1887–1898

[47] Sabarinathan R, Mularoni L, Deu-Pons J, Gonzalez-Perez A, López-Bigas N (2016) Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature 532:264–267

[48] Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A, Sankila A, Turunen J-P, Lundin M, Konsti J (2011) Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 30:3962–3976

[49] Sahu B, Laakso M, Pihlajamaa P, Ovaska K, Sinielnikov I, Hautaniemi S, Jänne OA (2013) FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 73:1570–1580

[50] Scheer S, Ackloo S, Medina TS, Schapira M, Li F, Ward JA, Lewis AM, Northrop JP, Richardson PL, Kaniskan HÜ (2019) A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. Nat Commun 10:19

[51] Sehrawat A, Gao L, Wang Y, Bankhead A 3rd, McWeeney SK, King CJ, Schwartzman J, Urrutia J, Bisson WH, Coleman DJ (2018) LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci USA 115:E4179–E4188

[52] Sekiya T, Muthurajan UM, Luger K, Tulin AV, Zaret KS (2009) Nucleosome-binding affinity as a primary determinant of the nuclear mobility of the pioneer transcription factor FoxA. Genes Dev 23:804–809

[53] Sérandour AA, Avner S, Percevault F, Demay F, Bizot M, Lucchetti-Miganeh C, Barloy-Hubler F, Brown M, Lupien M, Métivier R (2011) Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res 21:555–565

[54] Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953

[55] Song B, Park S-H, Zhao JC, Fong K-W, Li S, Lee Y, Yang YA, Sridhar S, Lu X, Abdulkadir SA (2019) Targeting FOXA1-mediated repression of TGF-β signaling suppresses castrationresistant prostate cancer progression. J Clin Invest 129:569–582

[56] Sutinen P, Rahkama V, Rytinki M, Palvimo JJ (2014) Nuclear mobility and activity of FOXA1 with androgen receptor are regulated by SUMOylation. Mol Endocrinol 28:1719–1728

[57] Szabo Q, Bantignies F, Cavalli G (2019) Principles of genome folding into topologically associating domains. Sci Adv 5: eaaw1668

[58] Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y, Qiu J, Liu W, Kaikkonen MU, Ohgi KA (2011) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474:390–394

[59] Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, Su H, Sun W, Chang H, Xu G(2009a) The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 41:125–129

[60] Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H, Lupien M (2009b) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138:245–256

[61] Wang S, Singh S, Katika M, Lopez-Aviles S, Hurtado A (2018) High throughput chemical screening reveals multiple regulatory proteins on FOXA1 in breast cancer cell lines. International Journal of Molecular Sciences 19:4123

[62] Watson PA, Arora VK, Sawyers CL (2015) Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15:701–711

[63] Whitington T, Gao P, Song W, Ross-Adams H, Lamb AD, Yang Y, Svezia I, Klevebring D, Mills IG, Karlsson R (2016) Gene regulatory mechanisms underpinning prostate cancer susceptibility. Nat Genet 48:387–397

[64] Wissmann M, Yin N, Müller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Günther T, Buettner R (2007) Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 9:347–353

[65] Wu Q, Heidenreich D, Zhou S, Ackloo S, Krämer A, Nakka K, Lima-Fernandes E, Deblois G, Duan S, Vellanki RN (2019) A chemical toolbox for the study of bromodomains and epigenetic signaling. Nat Commun 10:1915

[66] Xu B, Song B, Lu X, Kim J, Hu M, Zhao JC, Yu J (2019) Altered chromatin recruitment by FOXA1 mutations promotes androgen independence and prostate cancer progression. Cell Res 29:773–775

[67] Yamaguchi N, Shibazaki M, Yamada C, Anzai E, Morii M, Nakayama Y, Kuga T, Hashimoto Y, Tomonaga T, Yamaguchi N (2017) Tyrosine phosphorylation of the pioneer transcription factor FoxA1 promotes activation of estrogen signaling. J Cell Biochem 118:1453–1461

[68] Zhang X, Bailey SD, Lupien M (2014) Laying a solid foundation for Manhattan–’setting the functional basis for the post-GWAS era’. Trends Genet 30:140–149

[69] Zhang X, Cowper-Sal-lari R, Bailey SD, Moore JH, Lupien M (2012) Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus. Genome Research 22:1437–1446

[70] Zhou S, Hawley JR, Soares F, Grillo G, Teng M, Madani Tonekaboni SA, Hua JT, Kron KJ, Mazrooei P, Ahmed M (2020) Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer. Nat Commun 11:441

[71] Zhou S, Treloar AE, Lupien M (2016) Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations. Cancer Discov 6:1215–1229

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