Abstract
Background
Aberrant activation of androgen receptor signalling following castration therapy is a common clinical observation in prostate cancer (PCa). Earlier, we demonstrated the role of MYB overexpression in androgen-depletion resistance and PCa aggressiveness. Here, we investigated MYB-androgen receptor (AR) crosstalk and its functional significance.
Methods
Interaction and co-localization of MYB and AR were examined by co-immunoprecipitation and immunofluorescence analyses, respectively. Protein levels were measured by immunoblot analysis and enzyme-linked immunosorbent assay. The role of MYB in ligand-independent AR transcriptional activity and combinatorial gene regulation was studied by promoter-reporter and chromatin immunoprecipitation assays. The functional significance of MYB in castration resistance was determined using an orthotopic mouse model.
Results
MYB and AR interact and co-localize in the PCa cells. MYB-overexpressing PCa cells retain AR in the nucleus even when cultured under androgen-deprived conditions. AR transcriptional activity is also sustained in MYB-overexpressing cells in the absence of androgens. MYB binds and promotes AR occupancy to the KLK3 promoter. MYB-overexpressing PCa cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to shorter mice survival, compared to those carrying low-MYB-expressing prostate tumours.
Conclusions
Our findings reveal a novel MYB-AR crosstalk in PCa and establish its role in castration resistance.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
We confirm that all the data in this manuscript is original and we have access to the raw data files.
References
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.
Martinez-Breijo S, Chantada-Abal V, Aller-Rodriguez M, Bohorquez-Cruz M, Sacristan-Lista F, Ponce-Diaz J, et al. Castration resistance mechanisms in prostate cancer. Arch Esp Urol. 2018;71:628–38.
Kita Y, Goto T, Akamatsu S, Yamasaki T, Inoue T, Ogawa O, et al. Castration-resistant prostate cancer refractory to second-generation androgen receptor axis-targeted agents: opportunities and challenges. Cancers. 2018;10:345. https://doi.org/10.3390/cancers10100345.
Saranyutanon S, Deshmukh SK, Dasgupta S, Pai S, Singh S, Singh AP. Cellular and molecular progression of prostate cancer: models for basic and preclinical research. Cancers. 2020;12:2651. https://doi.org/10.3390/cancers12092651.
Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Nava Rodrigues D, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Invest. 2019;129:192–208.
Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. J Carcinogen. 2011;10:20.
Zhou Y, Ness SA. Myb proteins: angels and demons in normal and transformed cells. Front Biosci. 2011;16:1109–31.
Baker SJ, Ma’ayan A, Lieu YK, John P, Reddy MV, Chen EY, et al. B-myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development. Proc Natl Acad Sci USA. 2014;111:3122–7.
Li Y, Jin K, van Pelt GW, van Dam H, Yu X, Mesker WE, et al. c-Myb enhances breast cancer invasion and metastasis through the Wnt/beta-catenin/Axin2 pathway. Cancer Res. 2016;76:3364–75.
Tichy M, Knopfova L, Jarkovsky J, Pekarcikova L, Veverkova L, Vlcek P, et al. Overexpression of c-Myb is associated with suppression of distant metastases in colorectal carcinoma. Tumour Biol. 2016;37:10723–9.
Srivastava SK, Bhardwaj A, Singh S, Arora S, McClellan S, Grizzle WE. et al. Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: potential role in castration resistance. Carcinogenesis. 2012;33:1149–57.
Edwards J, Krishna NS, Witton CJ, Bartlett JM. Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin Cancer Res. 2003;9:5271–81.
Miree O, Srivastava SK, Khan MA, Sameeta F, Acharya S, Ndetan H. et al. Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer. Sci Rep. 2021;11:12901
Hijiya N, Zhang J, Ratajczak MZ, Kant JA, DeRiel K, Herlyn M, et al. Biologic and therapeutic significance of MYB expression in human melanoma. Proc Natl Acad Sci USA. 1994;91:4499–503.
Persson M, Andren Y, Mark J, Horlings HM, Persson F, Stenman G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci USA. 2009;106:18740–4.
Thompson MA, Rosenthal MA, Ellis SL, Friend AJ, Zorbas MI, Whitehead RH, et al. c-Myb down-regulation is associated with human colon cell differentiation, apoptosis, and decreased Bcl-2 expression. Cancer Res. 1998;58:5168–75.
Bhardwaj A, Srivastava SK, Singh S, Tyagi N, Arora S, Carter JE, et al. MYB Promotes desmoplasia in pancreatic cancer through direct transcriptional up-regulation and cooperative action of sonic hedgehog and adrenomedullin. J Biol Chem. 2016;291:16263–70.
Azim S, Zubair H, Srivastava SK, Bhardwaj A, Zubair A, Ahmad A, et al. Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer. Sci Rep. 2016;6:28446.
Srivastava SK, Bhardwaj A, Arora S, Singh S, Azim S, Tyagi N, et al. MYB is a novel regulator of pancreatic tumour growth and metastasis. Br J Cancer. 2015;113:1694–703.
Quintana AM, Liu F, O’Rourke JP, Ness SA. Identification and regulation of c-Myb target genes in MCF-7 cells. BMC Cancer. 2011;11:30.
Patel GK, Khan MA, Bhardwaj A, Srivastava SK, Zubair H, Patton MC, et al. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer. 2017;116:609–19.
Bhardwaj A, Srivastava SK, Singh S, Arora S, Tyagi N, Andrews J. et al. CXCL12/CXCR4 signaling counteracts docetaxel-induced microtubule stabilization via p21-activated kinase 4-dependent activation of LIM domain kinase 1. Oncotarget. 2014;5:11490–500.
Khan MA, Srivastava SK, Zubair H, Patel GK, Arora S, Khushman M, et al. Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer. J Biol Chem. 2020;295:8413–24.
Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell. 2013;23:35–47.
Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54:2577–81.
Bhardwaj A, Singh S, Srivastava SK, Honkanen RE, Reed E, Singh AP. Modulation of protein phosphatase 2A activity alters androgen-independent growth of prostate cancer cells: therapeutic implications. Mol Cancer Ther. 2011;10:720–31.
Pisano C, Tucci M, Di Stefano RF, Turco F, Scagliotti GV, Di Maio M, et al. Interactions between androgen receptor signaling and other molecular pathways in prostate cancer progression: current and future clinical implications. Crit Rev Oncol Hematol. 2021;157:103185.
Merseburger AS, Bellmunt J, Jenkins C, Parker C, Fitzpatrick JM. European Treatment Practices G. Perspectives on treatment of metastatic castration-resistant prostate cancer. Oncologist. 2013;18:558–67.
Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A’Hern R, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69:2912–8.
Reyes EE, VanderWeele DJ, Isikbay M, Duggan R, Campanile A, Stadler WM, et al. Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J Transl Med. 2014;12:313.
Chen T, Wang LH, Farrar WL. Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res. 2000;60:2132–5.
Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7:1541–50.
Schroder FH. Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. Eur Urol. 2008;53:1129–37.
Lang G, White JR, Argent-Katwala MJ, Allinson CG, Weston K. Myb proteins regulate the expression of diverse target genes. Oncogene. 2005;24:1375–84.
Sakura H, Kanei-Ishii C, Nagase T, Nakagoshi H, Gonda TJ, Ishii S. Delineation of three functional domains of the transcriptional activator encoded by the c-myb protooncogene. Proc Natl Acad Sci USA. 1989;86:5758–62.
Weston K, Bishop JM. Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb. Cell. 1989;58:85–93.
Ness SA. Myb binding proteins: regulators and cohorts in transformation. Oncogene. 1999;18:3039–46.
Kaspar P, Dvorakova M, Kralova J, Pajer P, Kozmik Z, Dvorak M. Myb-interacting protein, ATBF1, represses transcriptional activity of Myb oncoprotein. J Biol Chem. 1999;274:14422–8.
Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36:3–23.
Masoodi KZ, Xu Y, Dar JA, Eisermann K, Pascal LE, Parrinello E, et al. Inhibition of androgen receptor nuclear localization and castration-resistant prostate tumor growth by pyrroloimidazole-based small molecules. Mol Cancer Ther. 2017;16:2120–9.
Gan L, Chen S, Wang Y, Watahiki A, Bohrer L, Sun Z, et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res. 2009;69:8386–94.
Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, Dong H, et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol. 2018;1:100.
Li D, Tian G, Wang J, Zhao LY, Co O, Underill ZC. et al. Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival. Prostate. 2018;78:1140–56.
Li L, Chang W, Yang G, Ren C, Park S, Karantanos T, et al. Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Sci Signal. 2014;7:ra47.
Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22.
Sarvaiya PJ, Schwartz JR, Geng CD, Vedeckis WV. c-Myb interacts with the glucocorticoid receptor and regulates its level in pre-B-acute lymphoblastic leukemia cells. Mol Cell Endocrinol. 2012;361:124–32.
Thompson TC, Li L. New targets for resistant prostate cancer. Oncotarget. 2014;5:8816–7.
Todorova K, Metodiev MV, Metodieva G, Zasheva D, Mincheff M, Hayrabedyan S. miR-204 is dysregulated in metastatic prostate cancer in vitro. Mol Carcinogen. 2016;55:131–47.
Bhardwaj A, Singh S, Srivastava SK, Arora S, Hyde SJ, Andrews J, et al. Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model. Br J Cancer. 2014;110:2000–10.
Mansinho A, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets and treatment. Adv Exp Med Biol. 2018;1096:117–33.
Nonomura N, Takayama H, Nakayama M, Nakai Y, Kawashima A, Mukai M, et al. Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer. BJU Int. 2011;107:1918–22.
Pezaro C, Woo HH, Davis ID. Prostate cancer: measuring PSA. Intern Med J. 2014;44:433–40.
Acknowledgements
We would like to acknowledge the support of veterinarian and vivarium staff in our animal studies.
Funding information
We would like to acknowledge the funding from NIH/NCI [R01CA224306, U01CA185490 (to APS) and R01CA204801, R01CA231925 (to SS)] and USAMCI (to APS and SS).
Author information
Authors and Affiliations
Contributions
Conception and design: APS, SKS, MAK, SA, HZ and SS; development of methodology: APS, SKS, MAK, SA, HZ and SS; experiment and data generation: SKS, MAK, SA, HZ, SKD, GKP and JA; analysis and interpretation of data: APS, SKS, MAK, SA, HZ, SKD, JA, BW and JEC; writing original draft: SKS and APS; writing/reviewing and editing: MAK, APS, SKS, SA, SKD, HZ, GKP and JA; administrative and study supervision: APS and SS. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
The study involved no human subjects. Only the de-identified and archived human prostate cancer tissues were used under an exempt (category 4) protocol as determined by the University of South Alabama Institutional Review Board.
Consent for publication
Not applicable.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Srivastava, S.K., Khan, M.A., Anand, S. et al. MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer. Br J Cancer 126, 1205–1214 (2022). https://doi.org/10.1038/s41416-021-01641-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41416-021-01641-1
This article is cited by
-
Proto-oncogene c-Myb potentiates cisplatin resistance of ovarian cancer cells by downregulating lncRNA NKILA and modulating cancer stemness and LIN28A-let7 axis
Journal of Ovarian Research (2024)
-
From modulation of cellular plasticity to potentiation of therapeutic resistance: new and emerging roles of MYB transcription factors in human malignancies
Cancer and Metastasis Reviews (2024)
-
Second generation androgen receptor antagonists and challenges in prostate cancer treatment
Cell Death & Disease (2022)
-
The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer
Clinical and Translational Oncology (2022)