Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

Oncogene volume 27, pages 3313–3328 (2008)Cite this article

Abstract

Recent studies indicate that estrogen-related receptors (ERRs) are involved in similar estrogen receptor (ER) regulatory pathways and play roles in energy and lipid metabolism. Here, we analysed the functional role of ERRβ in prostate cancer cell growth regulation in an androgen-sensitive and androgen-insensitive prostate cancer cell lines. ERRβ was expressed in normal human prostates, but exhibited a reduced expression in prostate cancer lesions. Stable ERRβ expression suppressed significantly cell proliferation and tumorigenicity of LNCaP and DU145 cells, accompanied by an S-phase suppression and increased p21 expression. Reporter and chromatin immunoprecipitation assays showed that ERRβ could directly transactivate p21 gene promoter, which could be further enhanced by peroxisome proliferator-activated receptor-γ coactivator-1α. Truncation analysis showed that ERRβ-mediated p21 transactivation and prostate cancer cell growth inhibition required intact DNA-binding domain and AF2 domains in ERRβ. Interestingly, ERRβ displayed a cell cycle associated downregulated expression pattern in ERRβ-transduced and non-transduced cells. Finally, we showed that ERRβ-mediated growth inhibition could be potentiated by an ERRβ/γ agonist DY131. Knockdown of ERRβ by RNA interference could reduce the DY131-induced growth inhibition in prostate cancer cells. Taken together, our findings indicate that ERRβ performs a tumor suppressing function in prostate cancer cells, and targeting ERRβ could be a potential therapeutic strategy for prostate cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ . (2006). Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126: 789–799.

    Article  CAS  Google Scholar 

  • Castet A, Herledan A, Bonnet S, Jalaguier S, Vanacker JM, Cavaillès V . (2006). Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes. Mol Endocrinol 20: 1035–1047.

    Article  CAS  Google Scholar 

  • Chan PS, Chan LW, Xuan JW, Chin JL, Choi HL, Chan FL . (1999). In situ hybridization study of PSP94 (prostatic secretory protein of 94 amino acids) expression in human prostates. Prostate 41: 99–109.

    Article  CAS  Google Scholar 

  • Chen F, Zhang Q, McDonald T, Davidoff MJ, Bailey W, Bai C et al. (1999). Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. Gene 228: 101–109.

    Article  CAS  Google Scholar 

  • Cheung CP, Yu S, Wong KB, Chan LW, Lai FM, Wang X et al. (2005). Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. J Clin Endocrinol Metab 90: 1830–1844.

    Article  CAS  Google Scholar 

  • Fujimoto J, Nakagawa Y, Toyoki H, Sakaguchi H, Sato E, Tamaya T . (2005). Estrogen-related receptor expression in placenta throughout gestation. J Steroid Biochem Mol Biol 94: 67–69.

    Article  CAS  Google Scholar 

  • Giguère V . (2002). To ERR in the estrogen pathway. Trends Endocrinol Metab 13: 220–225.

    Article  Google Scholar 

  • Giguère V, Yang N, Segui P, Evans RM . (1988). Identification of a new class of steroid hormone receptors. Nature 331: 91–94.

    Article  Google Scholar 

  • Griffiths K . (2000). Estrogens and prostatic disease. International Prostate Health Council Study Group. Prostate 45: 87–100.

    Article  CAS  Google Scholar 

  • Ho E, Boileau TW, Bray TM . (2004). Dietary influences on endocrine-inflammatory interactions in prostate cancer development. Arch Biochem Biophys 428: 109–117.

    Article  CAS  Google Scholar 

  • Ho SM . (2004). Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem 91: 491–503.

    Article  CAS  Google Scholar 

  • Huang CY, Beliakoff J, Li X, Lee J, Li X, Sharma M et al. (2005). HZimp7, a novel PIAS-like protein, enhances androgen receptor-mediated transcription and interacts with SWI/SNF-like BAF complexes. Mol Endocrinol 19: 2915–2929.

    Article  CAS  Google Scholar 

  • Huss JM, Kopp RP, Kelly DP . (2002). Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-α and -γ. J Biol Chem 277: 40265–40274.

    Article  CAS  Google Scholar 

  • Huss JM, Torra IP, Staels B, Giguère V, Kelly DP . (2004). Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24: 9079–9091.

    Article  CAS  Google Scholar 

  • Ichida M, Nemoto S, Finkel T . (2002). Identification of a specific molecular repressor of the peroxisome proliferator-activator receptor γ coactivator-1α (PGC-1α). J Biol Chem 277: 50991–50995.

    Article  CAS  Google Scholar 

  • Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, Takahashi N et al. (2003). PPARγ coactivator 1β/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 100: 12378–12383.

    Article  CAS  Google Scholar 

  • Litvinov IV, Griend DJ, Antony L, Dalrymple S, De Marzo AM, Drake CG et al. (2006). Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells. Proc Natl Acad Sci USA 103: 15085–15090.

    Article  CAS  Google Scholar 

  • Liu Y . (2006). Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis 9: 230–234.

    Article  CAS  Google Scholar 

  • Lu D, Kiriyama Y, Lee KY, Giguère V . (2001). Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. Cancer Res 61: 6755–6761.

    CAS  Google Scholar 

  • Lui K, Huang Y, Choi HL, Yu S, Wong KB, Chen S et al. (2006). Molecular cloning and functional study of rat estrogen receptor-related receptor γ in rat prostatic cells. Prostate 66: 1600–1619.

    Article  CAS  Google Scholar 

  • Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J, Giguère V . (1997). Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-β. Nature 388: 778–782.

    Article  CAS  Google Scholar 

  • Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V . (2003). Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor α. Mol Cell Biol 23: 7947–7956.

    Article  CAS  Google Scholar 

  • Mitsunaga K, Araki K, Mizusaki H, Morohashi K, Haruna K, Nakagata N et al. (2004). Loss of PGC-specific expression of the orphan nuclear receptor ERR-β results in reduction of germ cell number in mouse embryos. Mech Dev 121: 237–246.

    Article  CAS  Google Scholar 

  • Pettersson K, Svensson K, Mattsson R, Carlsson B, Ohlsson R, Berkenstam A . (1996). Expression of a novel member of estrogen response element-binding nuclear receptors is restricted to the early stages of chorion formation during mouse embryogenesis. Mech Dev 54: 211–223.

    Article  CAS  Google Scholar 

  • Prins GS, Huang L, Birch L, Pu Y . (2006). The role of estrogens in normal and abnormal development of the prostate gland. Ann N Y Acad Sci 1089: 1–13.

    Article  CAS  Google Scholar 

  • Puigserver P, Spiegelman BM . (2003). Peroxisome proliferator-activator receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev 24: 78–90.

    Article  CAS  Google Scholar 

  • Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M et al. (2004). The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. Proc Natl Acad Sci USA 101: 6472–6477.

    Article  CAS  Google Scholar 

  • Sharma M, Li X, Wang Y, Zarnegar M, Huang CY, Palvimo JJ et al. (2003). HZimp10 is an androgen receptor co-activator and forms a complex with SUMO-1 at replication foci. EMBL J 22: 6101–6114.

    Article  CAS  Google Scholar 

  • Sladek R, Bader JA, Giguère V . (1997). The orphan nuclear receptor estrogen-related receptor α is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 17: 5400–5409.

    Article  CAS  Google Scholar 

  • Soriano FX, Liesa M, Bach D, Chan DC, Palacín M, Zorzano A . (2006). Evidence for a mitochondrial regulatory pathway defined peroxisome proliferator-activated receptor-γ coactivator-1α, estrogen-related receptor-α, and mitofusin 2. Diabetes 55: 1783–1791.

    Article  CAS  Google Scholar 

  • Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY, An DS et al. (2003). Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9: 493–501.

    Article  CAS  Google Scholar 

  • Tanaka S, Kunath T, Hadjantonakis AK, Nagy A, Rossant J . (1998). Promotion of trophoblast stem cell proliferation by FGF4. Science 282: 2072–2075.

    Article  CAS  Google Scholar 

  • Trapp T, Holsboer F . (1996). Nuclear orphan receptor as a repressor of glucocorticoid receptor transcriptional activity. J Biol Chem 271: 9879–9882.

    Article  CAS  Google Scholar 

  • Vanacker JM, Pettersson K, Gustafsson JÅ, Laudet V . (1999). Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrogen receptor (ER) α, but not by ERβ. EMBO J 18: 4270–4279.

    Article  CAS  Google Scholar 

  • Vankoningsloo S, Piens M, Lecocq C, Gilson A, De Pauw A, Renard P et al. (2005). Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose. J Lipid Res 46: 1133–1149.

    Article  CAS  Google Scholar 

  • Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A . (2007). Orphan nuclear receptor estrogen-related receptor α is essential for adaptive thermogenesis. Proc Natl Acad Sci USA 104: 1418–1423.

    Article  CAS  Google Scholar 

  • Waga S, Hannon GJ, Beach D, Stillman B . (1994). The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369: 574–578.

    Article  CAS  Google Scholar 

  • Wende AR, Huss JM, Schaeffer PJ, Giguère V, Kelly DP . (2005). PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol 25: 10684–10694.

    Article  CAS  Google Scholar 

  • Weihua Z, Warner M, Gustafsson JA . (2002). Estrogen receptor beta in the prostate. Mol Cell Endocrinol 193: 1–5.

    Article  Google Scholar 

  • Wright ME, Tsai MJ, Aebersold R . (2003). Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrinol 17: 1726–1737.

    Article  CAS  Google Scholar 

  • Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR et al. (1999). Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. Mol Endocrinol 13: 2151–2162.

    Article  CAS  Google Scholar 

  • Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M et al. (2006). Nuclear receptor expression links the circadian clock to metabolism. Cell 126: 801–810.

    Article  CAS  Google Scholar 

  • Yu DD, Forman BM . (2005). Identification of an agonist ligand for estrogen-related receptors ERRβ/γ. Bioorg Med Chem Lett 15: 1311–1313.

    Article  CAS  Google Scholar 

  • Yu S, Wang X, Ng CF, Chen S, Chan FL . (2007). ERRγ suppresses cell proliferation and tumor growth androgen-sensitive and androgen-insensitive prostate cancer cells and its implication as a therapeutic target for prostate cancer. Cancer Res 67: 4904–4914.

    Article  CAS  Google Scholar 

  • Zhou W, Liu Z, Wu J, Liu J, Hyder SM, Antoniou E et al. (2006). Identification and characterization of two novel splicing isoforms of human estrogen-related receptor β. J Clin Endocrinol Metab 91: 569–579.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by a Competitive Earmarked Research Grant from Research Grants Council (CUHK4411/06M) and Li Ka-Shing Institute of Health Sciences.

Author information

Authors and Affiliations

  1. Department of Anatomy, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    S Yu & F L Chan

  2. Department of Anatomy, The University of Hong Kong, Hong Kong, China

    Y C Wong, X H Wang & M T Ling

  3. Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    C F Ng

  4. Department of Surgical Research, The Beckman Research Institute of the City of Hope, Duarte, CA, USA

    S Chen

Authors
  1. S Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y C Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M T Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C F Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F L Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F L Chan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, S., Wong, Y., Wang, X. et al. Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer. Oncogene 27, 3313–3328 (2008). https://doi.org/10.1038/sj.onc.1210986

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210986

Keywords

This article is cited by

Search

Advanced search

Quick links