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.

Key words： 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. https://doi.org/10.1038/s41588-020-0681-7

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. https://doi.org/10.1158/0008-5472.CAN-19-3447

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