MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen
Autoři:
Hannah Weber aff001; Rachel Ruoff aff001; Michael J. Garabedian aff001
Působiště autorů:
Departments of Microbiology and Urology, New York University School of Medicine, New York, New York, United States of America
aff001
Vyšlo v časopise:
MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen. PLoS Genet 17(1): e1008540. doi:10.1371/journal.pgen.1008540
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008540
Souhrn
Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.
Klíčová slova:
Prostate cancer – Acetylation – Androgens – Ethanol – Gene expression – Small interfering RNA – Transcription factors – Transcriptional control
Zdroje
1. Chan S, Dehm S. Constitutive activity of the androgen receptor. Advances in Pharmacology. 2014;70:327–66.
2. Claessens F, Helsen C, Prekovic S, Broeck TVd, Spans L, Poppel HV, et al. Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol. 2014;11:712–16.
3. Harris W, Mostaghel E, Nelson P, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nature Clinical Practice Urology. 2009;6:76–85.
4. Shen M, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24:1967–2000.
5. Watson P, Arora V, Sawyers C. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nature Reviews Cancer. 2015;15:701–11.
6. Chandrasekar T, Yang J, Gao A, Evans C. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Translational Andrology and Urology. 2015;4:365–80.
7. Labbe D, Brown M. Transcriptional Regulation in Prostate Cancer. Cold Spring Harbor Perspectives in Medicine. 2018;8:a030437.
8. Dai C, Heemrs H, Sharifi N. Androgen Signaling in Prostate Cancer. Cold Spring Harbor Perspectives in Medicine. 2017;7:a030452.
9. Heemers H, Tindall D. Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex. Endocr Rev. 2007;28:778–808.
10. Debes J, Sebo T, Lohse C, Murphy L, Haugen D, Tindall D. p300 in prostate cancer proliferation and progression. Cancer Research. 2003;63:7638–40.
11. Fu M, Wang C, Reutens A, Wang J, Angeletti R, Siconolfi-Baez L, et al. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. Journal of Biological Chemistry. 2000;275:20853–60.
12. Ianculescu I, Wu D, Siegmund K, Stallcup M. Selective roles for cAMP response element-binding protein binding protein and p300 protein as coregulators for androgen-regulated gene expression in advanced prostate cancer cells. Journal of Biological Chemistry. 2012;287:4000–13.
13. Jin L, Garcia J, Chan E, Cruz Cdl, Segal E, Merchant M, et al. Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer. Cancer Research. 2017;77:5564–75.
14. Urbanucci A, Barfeld S, Kytölä V, Itkonen H, Coleman I, Vodák D, et al. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Reports. 2017;19:2045–59.
15. Cai L, Tsai Y, Wang P, Wang J, Li D, Fan H, et al. ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. Molecular Cell. 2018;72:341–54.
16. Asangani I, Dommeti V, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.
17. Piha-Paul S, Sachdev J, Barve M, PLoRusso, Szmulewitz R, Patel S, et al. First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors. Clinical Cancer Research. 2019;Epub ahead of print.
18. Massie C, Adryan B, Barbosa-Morais N, Lynch A, Tran M, Neal D, et al. New androgen receptor genomic targets show an interaction with the ETS1 transcription factor. EMBO Reports. 2007;8:871–8.
19. Makkonen H, Jääskeläinen T, Pitkänen-Arsiola T, Rytinki M, Waltering K, Mättö M, et al. Identification of ETS-like transcription factor 4 as a novel androgen receptor target in prostate cancer cells. Oncogene. 2008;27:4865–76.
20. Kawahara T, Aljarah A, Shareef H, Inoue S, Ide H, Patterson J, et al. Silodosin inhibits prostate cancer cell growth via ELK1 inactivation and enhances the cytotoxic activity of gemcitabine. The Prostate. 2016;76:744–56.
21. Smith A, Findlay V, Bandurraga S, Kistner-Griffin E, Spruill L, Liu A, et al. ETS1 transcriptional activity is increased in advanced prostate cancer and promotes the castrate-resistant phenotype. Carcinogenesis. 2012;33:572–80.
22. Yu J, Yu J, Mani R, Cao Q, Brenner C, Cao X, et al. An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression. Cancer Cell. 2010;17:443–54.
23. Patki M, Chari V, Sivakumaran S, Gonit M, Trumbly R, Ratnam M. The ETS domain transcription factor ELK1 directs a critical component of growth signaling by the androgen receptor in prostate cancer cells. Journal of Biological Chemistry. 2013;288:11047–65.
24. Rosati R, Patki M, Chari V, Dakshnamurthy S, McFall T, Saxton J, et al. The Amino-terminal Domain of the Androgen Receptor Co-opts Extracellular Signal-regulated Kinase (ERK) Docking Sites in ELK1 Protein to Induce Sustained Gene Activation That Supports Prostate Cancer Cell Growth. Journal of Biological Chemistry. 2016;291:25983–98.
25. Wolf I, Heitzer M, Grubisha M, DeFranco D. Coactivators and nuclear receptor transactivation. J Cell Biochem. 2008;104:1580–6.
26. Imberg-Kazdan K, Ha S, Greenfield A, Poultney C, Bonneau R, Logan S, et al. A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells. Genome Research. 2013;23:581–91.
27. Khattabi LE, Zhao H, Kalchschmidt J, Young N, Jung S, Blerkom PV, et al. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers. Cell. 2019;178:1145–58.
28. Robinson D, Allen EV,. . . ., Sawyers C, Chinnaiyan A. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell. 2015;161:1215–122.
29. Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver B, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.
30. Yu S, Wang Y, Yuan H, Zhao H, Lv W, Chen J, et al. Knockdown of Mediator Complex Subunit 19 Suppresses the Growth and Invasion of Prostate Cancer Cells. PLoS One. 2017;12:e0171134.
31. Bello D, Webber M, Kleinman H, Wartinger D, Rhim J. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis. 1997;18:1215–23.
32. Xiong X, Schober M, Tassone E, Khodadadi-Jamayran A, Sastre-Perona A, Zhou H, et al. KLF4, A Gene Regulating Prostate Stem Cell Homeostasis, Is a Barrier to Malignant Progression and Predictor of Good Prognosis in Prostate Cancer. Cell Rep. 2018;25(11):3006–20 e7. doi: 10.1016/j.celrep.2018.11.065 30540935; PubMed Central PMCID: PMC6405286.
33. Paschalis A, Sharp A, Welti J, Neeb A, Raj G, Luo J, et al. Alternative splicing in prostate cancer. Nature Reviews Clinical Oncology. 2018;15:663–75.
34. Tran C, Ouk S, Clegg N, Chen Y, Watson P, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.
35. Wu J, Shao C, Li X, Li Q, Hu P, Shi C, et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. Journal of Clinical Investigation. 2014;124:2891–908.
36. Wu JB, Yin L, Shi C, Li Q, Duan P, Huang JM, et al. MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions. Cancer Cell. 2017;31(3):368–82. doi: 10.1016/j.ccell.2017.02.003 28292438.
37. Gaur S, Gross M, Liao C, Qian B, Shih J. Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. The Prostate. 2019;79:667–77.
38. Liao C, Lin T, Li P, Geary L, Chen K, Vaikari V, et al. Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate. Oncogene. 2018;37:5175–90.
39. Ou X, Chen K, Shih J. Glucocorticoid and androgen activation of monoamine oxidase A is regulated differently by R1 and Sp1. Journal of Biological Chemistry. 2006;281:21512–25.
40. Liu Y, Gong Z, Sun L, Li X. FOXM1 and androgen receptor co-regulate CDC6 gene transcription and DNA replication in prostate cancer cells. Biochimica et Biophysica Acta—Gene Regulatory Mechanisms. 2014;1839:297–305.
41. Liu Y, Liu Y, Yuan B, Yin L, Peng Y, Yu X, et al. FOXM1 promotes the progression of prostate cancer by regulating PSA gene transcription. Oncotarget. 2017;8:17027–37.
42. Yang Y, Yu J. Current perspectives on FOXA1 regulation of androgen receptor signaling and prostate cancer. Genes and Diseases. 2015;2:144–51.
43. Li Y, Vongsangnak W, Chen L, Shen B. Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression. BMC Medical Genomics. 2014;7:S3 epub.
44. Diao X, Chen X, Pi Y, Zhang Y, Wang F, Liu P, et al. Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1. Oncology Reports. 2018;40:1174–84.
45. Lu S, Jenster G, Epner D. Androgen induction of cyclin-dependent kinase inhibitor p21 gene: role of androgen receptor and transcription factor Sp1 complex. Molecular Endocrinology. 2000;14:753–60.
46. Chen Z, Zhang C, Wu D, Chen H, Rorick A, Zhang X, et al. Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth. EMBO Journal. 2011;30:2405–19.
47. Wang Q, Sharma D, Ren Y, Fondell J. A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression. Journal of Biological Chemistry. 2002;277:42852–8.
48. True L, Coleman I, Hawley S, Huang C, Gifford D, Coleman R, et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. PNAS. 2006;103:10991–6.
49. Peehl D, Coram M, Khine H, Reese S, Nolley R, Zhao H. The significance of monoamine oxidase-A expression in high grade prostate cancer. Journal of Urology. 2008;180:2206–11.
50. White T, Kwon E, Fu R, Lucas J, Ostrander E, Stanford J, et al. The monoamine oxidase A gene promoter repeat and prostate cancer risk. The Prostate. 2012;72:1622–7.
51. Li Q, Yang S, Maeda Y, Sladek F, Sharrocks A, Martins-Green M. MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300. EMBO Journal. 2003;22:281–91.
52. Janknecht R, Nordheim A. MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP. Biochemical and Biophysical Research Communications. 1996;228:831–7.
53. Robinson P, Trnka M, Bushnell D, Davis R, Mattei P, Burlingame A, et al. Structure of a Complete Mediator-RNA Polymerase II Pre-Initiation Complex. Cell. 2016;166:1411–22.
54. Yuan C-X, Ito M, Fondell J, Fu Z-Y, Roeder R. The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proceedings of the National Academy of Sciences. 1998;95:7939–44.
55. Rasool R, Natesan R, Deng Q, Aras S, Lal P, Effron SS, et al. CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer Discovery. 2019;Epub ahead of print.
56. Vijayvargia R, May M, Fondell J. A Coregulatory Role for the Mediator Complex in Prostate Cancer Cell Proliferation and Gene Expression. Cancer Research. 2007;67:4034–41.
57. He G, Hu J, Zhou L, Zhu X, Xin S, Zhang D, et al. The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer. British Journal of Cancer. 2016;115:1367–78.
58. Zhang X, Fan Y, Liu B, Qi X, Guo Z, Li L. Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression. Breast Cancer. 2017;24:433–41.
59. Liu B, Qi X, Zhang X, Gao D, Fang K, Guo Z, et al. Med19 is involved in chemoresistance by mediating autophagy through HMGB1 in breast cancer. Journal of Cellular Biochemistry. 2019;120:507–18.
60. Xu Y, Liang Z, Li C, Yang Z, Chen L. LCMR1 interacts with DEK to suppress apoptosis in lung cancer cells. Molecular Medicine Reports. 2017;16:4159–64.
61. Agaësse G, Barbollat-Boutrand L, Sulpice E, Bhajun R, Kharbili ME, Berthier-Vergnes O, et al. A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. Oncogene. 2016;36:446–57.
62. Sun M, Jiang R, Li J, Luo S, Gao H, Jin C, et al. MED19 promotes proliferation and tumorigenesis of lung cancer. Molecular and Cellular Biology. 2011;355:27–33.
63. Zhang Y, Li P, Hu J, Zhao L, Li J, Ma R, et al. Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance. Biochemical and Biophysical Research Communications. 2019;508:210–6.
64. Ryan MC, Zeeberg BR, Caplen NJ, Cleland JA, Kahn AB, Liu H, et al. SpliceCenter: a suite of web-based bioinformatic applications for evaluating the impact of alternative splicing on RT-PCR, RNAi, microarray, and peptide-based studies. BMC Bioinformatics. 2008;9:313. Epub 2008/07/22. doi: 10.1186/1471-2105-9-313 18638396; PubMed Central PMCID: PMC2491637.
65. Parsons BD, Schindler A, Evans DH, Foley E. A direct phenotypic comparison of siRNA pools and multiple individual duplexes in a functional assay. PLoS One. 2009;4(12):e8471. Epub 2009/12/31. doi: 10.1371/journal.pone.0008471 20041186; PubMed Central PMCID: PMC2793519.
66. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013;14:128. doi: 10.1186/1471-2105-14-128 23586463; PubMed Central PMCID: PMC3637064.
67. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–7. doi: 10.1093/nar/gkw377 27141961; PubMed Central PMCID: PMC4987924.
68. Fonseca GJ, Tao J, Westin EM, Duttke SH, Spann NJ, Strid T, et al. Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages. Nat Commun. 2019;10(1):414. doi: 10.1038/s41467-018-08236-0 30679424; PubMed Central PMCID: PMC6345992.
Článek vyšel v časopise
PLOS Genetics
2021 Číslo 1
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen
- A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant
- Population structure of indigenous inhabitants of Arabia
- Epithelial cell-turnover ensures robust coordination of tissue growth in Drosophila ribosomal protein mutants
