Skip to main content

Advertisement

Log in

Estrogen-related receptor alpha in select host functions and cancer: new frontiers

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Eukaryotic gene expression is under the tight control of transcription factors, which includes the estrogen-related receptor alpha (ERRα). The endogenous ligand(s) acting as ERRα agonist has not been identified and confirmed. ERRα is a prominent member of the nuclear receptors super-family with major roles in energy metabolism, including immunity, cell growth, proliferation and differentiation and a host of other functions in animals. The actions exerted by ERRα towards gene expression regulation are often in association with other transcriptional factors, receptors and signal mediators. Metabolic regulation by ERRα is known for some time that has tremendous impact on host biology like autophagy, angiogenesis, mitochondrial activity, including lipid metabolism. Cellular metabolism and cancer has intricate relationship. On account of the participation of ERRα in metabolism, it has been implicated in various types of cancer onset and progression. In a number of findings, ERRα has been demonstrated to influence several types of cancers, exhibiting as a negative prognostic marker for many. Such diverse role associated with ERRα is due to its interaction with numerous transcriptional factors and other signalling pathways that culminate in providing optimal gene regulation. These observations points to the crucial regulatory roles of ERRα in health and disease. In this article, some of the new findings on the influence of ERRα in host metabolism and biology including cancer, shall be reviewed that will provide a concise understanding of this receptor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Data availability

Enquiries about data availability should be directed to the authors.

References

  1. Giguere V (1999) Orphan nuclear receptors: from gene to function. Endocr Rev 20:689–725

    CAS  PubMed  Google Scholar 

  2. Giguere V (2008) Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev 29:677–696

    Article  CAS  PubMed  Google Scholar 

  3. Likhite N, Yadav V, Milliman EJ et al (2019) Loss of estrogen-related receptor alpha facilitates angiogenesis in endothelial cells. Mol Cell Biol 39:e00411-e418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xia H, Dufour CR, Giguere V (2019) ERRalpha as a bridge between transcription and function: role in liver metabolism and disease. Front Endocrinol (Lausanne) 10:206

    Article  Google Scholar 

  5. Sladek R, Giguere V (2000) Orphan nuclear receptors: an emerging family of metabolic regulators. Adv Pharmacol 47:23–87

    Article  CAS  PubMed  Google Scholar 

  6. Bookout AL, Jeong Y, Downes M et al (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vega RB, Kelly DP (1997) A role for estrogen-related receptor alpha in the control of mitochondrial fatty acid beta-oxidation during brown adipocyte differentiation. J Biol Chem 272:31693–31699

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alaynick WA (2008) Nuclear receptors, mitochondria and lipid metabolism. Mitochondrion 8:329–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Luo J, Sladek R, Carrier J et al (2003) Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 23:7947–7956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ju D, He J, Zhao L et al (2012) Estrogen related receptor alpha-induced adipogenesis is PGC-1beta-dependent. Mol Biol Rep 39:3343–3354

    Article  CAS  PubMed  Google Scholar 

  12. Ijichi N, Ikeda K, Horie-Inoue K et al (2007) Estrogen-related receptor alpha modulates the expression of adipogenesis-related genes during adipocyte differentiation. Biochem Biophys Res Commun 358:813–818

    Article  CAS  PubMed  Google Scholar 

  13. Ramjiawan A, Bagchi RA, Albak L et al (2013) Mechanism of cardiomyocyte PGC-1α gene regulation by ERRα. Biochem Cell Biol 91:148–154

    Article  CAS  PubMed  Google Scholar 

  14. Ariazi EA, Clark GM, Mertz JE (2002) Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res 62:6510–6518

    CAS  PubMed  Google Scholar 

  15. Heck S, Rom J, Thewes V et al (2009) Estrogen-related receptor alpha expression and function is associated with the transcriptional coregulator AIB1 in breast carcinoma. Cancer Res 69:5186–5193

    Article  CAS  PubMed  Google Scholar 

  16. Zou C, Yu S, Xu Z et al (2014) ERRa augments HIF-1 signalling by directly interacting with HIF-1a in normoxic and hypoxic prostate cancer cells. J Pathol 233:61–73

    Article  CAS  PubMed  Google Scholar 

  17. Mirebeau-Prunier D, Le Pennec S, Jacques C et al (2013) Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS ONE 8:e58683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ranhotra HS (2015) Estrogen-related receptor alpha and mitochondria: tale of the titans. J Recept Signal Transduct Res 35:386–390

    Article  CAS  PubMed  Google Scholar 

  19. Samarut J, Plateroti M (2018) Thyroid hormone receptors: several players for one hormone and multiple functions. Methods Mol Biol 1801:1–8

    Article  CAS  PubMed  Google Scholar 

  20. Singh BK, Sinha RA, Tripathi M et al (2018) Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci Signal 11(536):5855

    Article  Google Scholar 

  21. Bender T, Martinou JC (2016) The mitochondrial pyruvate carrier in health and disease: to carry or not to carry? Biochim Biophys Acta 1863:2436–2442

    Article  CAS  PubMed  Google Scholar 

  22. Koh E, Kim YK, Shin D et al (2018) MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis. Biochem J 475(10):1687–1699

    Article  CAS  PubMed  Google Scholar 

  23. Ricquier D (2017) UCP1, the mitochondrial uncoupling protein of brown adipocyte: a personal contribution and a historical perspective. Biochimie 134:3–8

    Article  CAS  PubMed  Google Scholar 

  24. Christian M (2013) Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue. Horm Mol Biol Clin Investig 14(3):87–97

    CAS  PubMed  Google Scholar 

  25. Gantner ML, Hazen BC, Eury E et al (2016) Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function. Endocrinology 157(12):4770–4781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Griveau A, Devailly G, Eberst L et al (2016) The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action. Oncogene 35(38):5033–5042

    Article  CAS  PubMed  Google Scholar 

  27. Masuda T, Wada Y, Kawamura S (2016) ES1 is a mitochondrial enlarging factor contributing to form mega-mitochondria in zebrafish cones. Sci Rep 6:22360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Audet-Walsh E, Giguere V (2015) The multiple universes of estrogen-related receptor alpha and gamma in metabolic control and related diseases. Acta Pharmacol Sin 36:51–61

    Article  CAS  PubMed  Google Scholar 

  29. Ranhotra HS (2010) The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions. J Recept Signal Transduct Res 30:193–205

    Article  CAS  PubMed  Google Scholar 

  30. Soriano FX, Liesa M, Bach D et al (2006) Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55:1783–1791

    Article  CAS  PubMed  Google Scholar 

  31. Sonoda J, Laganière J, Mehl IR et al (2007) Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ induced host defense. Genes Dev 21:1909–1920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu YM, Chen ZJ, Jiang GM et al (2016) Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways. Oncotarget 7:12568–12581

    Article  PubMed  PubMed Central  Google Scholar 

  33. Vernier M, Dufour CR, McGuirk S et al (2020) Estrogen-related receptors are targetable ROS sensors. Genes Dev 34:544–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Migliavacca E, Tay SKH, Patel HP et al (2019) Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nat Commun 10(1):5808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ranhotra HS (2015) Estrogen-related receptor alpha and cancer: axis of evil. J Recept Signal Transduct Res 35:505–508

    Article  CAS  PubMed  Google Scholar 

  36. Zhang LD, Chen L, Zhang M et al (2015) Downregulation of ERRα inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signalling pathway. Eur J Pharmacol 769:167–176

    Article  CAS  PubMed  Google Scholar 

  37. Hu JZ, Long H, Wu TD et al (2015) The effect of ERRα on the regulation of angiogenesis after spinal cord injury. Neurosci 29:570–580

    Article  Google Scholar 

  38. Sopariwala DH, Likhite N, Pei G et al (2021) Estrogen-related receptor α is involved in angiogenesis and skeletal muscle revascularization in hindlimb ischemia. FASEB J 35(5):e21480

    Article  CAS  PubMed  Google Scholar 

  39. Wu Y, Zhang Q, Zhang R (2017) Kaempferol targets estrogen-related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions. Exp Ther Med 14(6):5576–5582

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tang D, Kang R, Berghe TV et al (2019) The molecular machinery of regulated cell death. Cell Res 2:347–364

    Article  Google Scholar 

  41. Kim SY, Yang CS, Lee HM et al (2018) ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. Autophagy 14:152–168

    Article  CAS  PubMed  Google Scholar 

  42. Paik S, Kim JK, Chung C et al (2018) Autophagy: a new strategy for host-directed therapy of tuberculosis. Virulence 15:1–12

    Google Scholar 

  43. Suresh SN, Chavalmane AK, Pillai M et al (2018) Modulation of autophagy by a small molecule inverse agonist of ERRα is neuroprotective. Front Mol Neurosci 11:109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kim S, Lee JY, Shin SG et al (2020) ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota. Autophagy 15:1–20

    Google Scholar 

  45. Xia H, Dufour CR, Giguère V (2019) ERRα as a bridge between transcription and function: role in liver metabolism and disease. Front Endocrinol 10:206

    Article  Google Scholar 

  46. Senga S, Kawaguchi K, Kobayashi N et al (2018) A novel fatty acid-binding protein 5-estrogen-related receptor α signaling pathway promotes cell growth and energy metabolism in prostate cancer cells. Oncotarget 9:31753–31770

    Article  PubMed  PubMed Central  Google Scholar 

  47. B’chir W, Dufour CR, Ouellet C et al (2018) Divergent role of estrogen-related receptor α in lipid- and fasting-induced hepatic steatosis in mice. Endocrinology 159:2153–2164

    Article  CAS  PubMed  Google Scholar 

  48. Ranhotra HS (2009) Up-regulation of orphan nuclear estrogen-related receptor alpha expression during long-term caloric restriction in mice. Mol Cell Biochem 332:59–65

    Article  CAS  PubMed  Google Scholar 

  49. Yang M, Liu Q, Huang T et al (2020) Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development. Theranostics 10(24):10874–10891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen CY, Li Y, Zeng N et al (2021) Inhibition of estrogen-related receptor α blocks liver steatosis and steatohepatitis and attenuates triglyceride biosynthesis. Am J Pathol 191(7):1240–1254

    Article  CAS  PubMed  Google Scholar 

  51. Chen L, Wu M, Zhang S et al (2019) Estrogen-related receptor γ regulates hepatic triglyceride metabolism through phospholipase A2 G12B. FASEB J 33:7942–7952

    Article  CAS  PubMed  Google Scholar 

  52. Hauck AK, Huang Y, Hertzel AV et al (2019) Adipose oxidative stress and protein carbonylation. J Biol Chem 294:1083–1088

    Article  CAS  PubMed  Google Scholar 

  53. Hauck AK, Zhou T, Hahn W et al (2018) Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA-binding domain of nuclear zinc finger proteins. J Biol Chem 293:13464–13476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ranhotra HS (2018) The estrogen-related receptors in metabolism and cancer: newer insights. J Recept Signal Transduct Res 38:95–100

    Article  CAS  PubMed  Google Scholar 

  55. Yoriki K, Mori T, Kokabu T et al (2019) Estrogen-related receptor alpha induces epithelial-mesenchymal transition through cancer-stromal interactions in endometrial cancer. Sci Rep 9:6697

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wang S, Huo X (2021) Comprehensive analysis of ESRRA in endometrial cancer. Technol Cancer Res Treat 20:1533033821992083

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang M, Chen L, Mao X et al (2020) ERRα inhibitor acts as a potential agonist of PPARγ to induce cell apoptosis and inhibit cell proliferation in endometrial cancer. Aging (Albany NY) 12(22):23029–23046

    CAS  Google Scholar 

  58. Huang X, Wang X, Shang J et al (2018) Estrogen related receptor alpha triggers the migration and invasion of endometrial cancer cells via up regulation of TGFB1. Cell Adhes Migr 12:538–547

    Article  CAS  Google Scholar 

  59. Matsushima H, Mori T, Ito F et al (2016) Anti-tumor effect of estrogen-related receptor alpha knockdown on uterine endometrial cancer. Oncotarget 7:34131–34148

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ye X, Guo J, Zhang H et al (2019) The enhanced expression of estrogen-related receptor α in human bladder cancer tissues and the effects of estrogen-related receptor α knockdown on bladder cancer cells. J Cell Biochem 120:13841–13852

    Article  CAS  PubMed  Google Scholar 

  61. Kim S, Lee AJ, Yeo MK et al (2018) Clinicopathological profiling of LC3B, an autophagy marker, and ESRRA (estrogen-related receptor-alpha) in muscle-invasive bladder cancer. Anticancer Res 38:2429–2437

    CAS  PubMed  Google Scholar 

  62. Vargas G, Bouchet M, Bouazza L et al (2019) ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. Oncogene 38:950–964

    Article  CAS  PubMed  Google Scholar 

  63. Kumari K, Adhya AK, Rath AK et al (2018) Estrogen-related receptors alpha, beta and gamma expression and function is associated with transcriptional repressor EZH2 in breast carcinoma. BMC Cancer 18:690

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kahl P, Gullotti L, Heukamp LC et al (2006) Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res 66:11341–11347

    Article  CAS  PubMed  Google Scholar 

  65. Carnesecchi J, Forcet C, Zhang L et al (2017) ERRα induces H3K9 demethylation by LSD1 to promote cell invasion. Proc Natl Acad Sci USA 114:3909–3914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Carnesecchi J, Cerutti C, Vanacker JM et al (2017) ERRα protein is stabilized by LSD1 in a demethylation-independent manner. PLoS ONE 12:e0188871

    Article  PubMed  PubMed Central  Google Scholar 

  67. Vernier M, McGuirk S, Dufour CR et al (2020) Inhibition of DNMT1 and ERRα crosstalk suppresses breast cancer via de-repression of IRF4. Oncogene 39(41):6406–6420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ma JH, Qi J, Lin SQ et al (2019) STAT3 targets ERR-α to promote epithelial-mesenchymal transition, migration, and invasion in triple-negative breast cancer cells. Mol Cancer Res 17(11):2184–2195

    Article  CAS  PubMed  Google Scholar 

  69. Bouchet M, Lainé A, Boyault C et al (2020) ERRα expression in bone metastases leads to an exacerbated antitumor immune response. Cancer Res 80(13):2914–2926

    Article  CAS  PubMed  Google Scholar 

  70. Liang R, Lin Y, Yuan CL et al (2018) High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer. Oncol Lett 15:5933–5939

    PubMed  PubMed Central  Google Scholar 

  71. Ding S, Tang Z, Jiang Y et al (2017) IL-8 is involved in estrogen-related receptor α-regulated proliferation and migration of colorectal cancer cells. Dig Dis Sci 62:3438–3446

    Article  CAS  PubMed  Google Scholar 

  72. Boudjadi S, Bernatchez G, Beaulieu JF et al (2013) Control of the human osteopontin promoter by ERRα in colorectal cancer. Am J Pathol 183:266–276

    Article  CAS  PubMed  Google Scholar 

  73. Bernatchez G, Giroux V, Lassalle T et al (2013) ERRα metabolic nuclear receptor controls growth of colon cancer cells. Carcinogenesis 34:2253–2261

    Article  CAS  PubMed  Google Scholar 

  74. De Vitto H, Ryu J, Calderon-Aparicio A et al (2020) Estrogen-related receptor alpha directly binds to p53 and cooperatively controls colon cancer growth through the regulation of mitochondrial biogenesis and function. Cancer Metab 8(1):28

    Article  PubMed  PubMed Central  Google Scholar 

  75. Xu Z, Wang Y, Xiao G et al (2018) Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer. Oncogene 37:6259–6274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fradet A, Bouchet M, Delliaux C et al (2016) Estrogen-related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone. Oncotarget 7:77071–77086

    Article  PubMed  PubMed Central  Google Scholar 

  77. Torrano V, Valcarcel-Jimenez L, Cortazar AR et al (2016) The metabolic co-regulator PGC1α suppresses prostate cancer metastasis. Nat Cell Biol 18:645–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Valcarcel-Jimenez L, Macchia A, Crosas-Molist E et al (2019) PGC1α suppresses prostate cancer cell invasion through ERRα transcriptional control. Cancer Res 79(24):6153–6165

    Article  CAS  PubMed  Google Scholar 

  79. Xu Z, Ma T, Zhou J et al (2020) Nuclear receptor ERRα contributes to castration-resistant growth of prostate cancer via its regulation of intratumoral androgen biosynthesis. Theranostics 10(9):4201–4216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhou J, Wang Y, Wu D et al (2021) Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer. Oncogene 40(15):2625–2634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Schoepke E, Billon C, Haynes KM et al (2020) A selective ERRα/γ inverse agonist, SLU-PP-1072, inhibits the Warburg effect and induces apoptosis in prostate cancer cells. ACS Chem Biol 15(9):2338–2345

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is thankful to the Department of Biochemistry, St. Edmund’s College, Shillong, India for providing research support.

Funding

No funding is associated with this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Harmit S. Ranhotra.

Ethics declarations

Conflict of interest

The author has nothing to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ranhotra, H.S. Estrogen-related receptor alpha in select host functions and cancer: new frontiers. Mol Cell Biochem 477, 1349–1359 (2022). https://doi.org/10.1007/s11010-022-04380-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04380-w

Keywords

Navigation