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.

  • Article
  • Published:

Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks

Oncogene volume 43, pages 2431–2446 (2024)Cite this article

Subjects

Abstract

Mortalin (encoded by HSPA9) is a mitochondrial chaperone often overexpressed in cancer through as-yet-unknown mechanisms. By searching different RNA-sequencing datasets, we found that ESRRA is a transcription factor highly correlated with HSPA9 in thyroid cancer, especially in follicular, but not C cell-originated, tumors. Consistent with this correlation, ESRRA depletion decreased mortalin expression only in follicular thyroid tumor cells. Further, ESRRA expression and activity were relatively high in thyroid tumors with oncocytic characteristics, wherein ESRRA and mortalin exhibited relatively high functional overlap. Mechanistically, ESRRA directly regulated HSPA9 transcription through a novel ESRRA-responsive element located upstream of the HSPA9 promoter. Physiologically, ESRRA depletion suppressed thyroid tumor cell survival via caspase-dependent apoptosis, which ectopic mortalin expression substantially abrogated. ESRRA depletion also effectively suppressed tumor growth and mortalin expression in the xenografts of oncocytic or ESRRA-overexpressing human thyroid tumor cells in mice. Notably, our Bioinformatics analyses of patient data revealed two ESRRA target gene clusters that contrast oncocytic-like and anaplastic features of follicular thyroid tumors. These findings suggest that ESRRA is a tumor-specific regulator of mortalin expression, the ESRRA-mortalin axis has higher significance in tumors with oncocytic characteristics, and ESRRA target gene networks can refine molecular classification of thyroid cancer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Correlation analysis of ESRRA and HSPA9 in different thyroid tumor subtypes.
Fig. 2: ESRRA depletion suppresses thyroid tumor cell viability through caspase-dependent apoptosis.
Fig. 3: shRNA non-targetable ESRRA and mortalin overexpression rescues ESRRA-depleted cells.
Fig. 4: ESRRA increases HSPA9 expression through an interaction with HSPA9 promoter in follicular cell-originated tumor cells.
Fig. 5: ESRRA increases the activity of HSPA9 promoter through an ERRE.
Fig. 6: ESRRA expression and activity in different thyroid tumor subtypes.
Fig. 7: A molecular subtyping using ESRRA signature genes.
Fig. 8: ESRRA knockdown suppresses the growth of XTC.UC1 and FTC133 xenografts in athymic nude mice.

Similar content being viewed by others

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and the Supplementary Materials.

References

  1. National Cancer Institute: Surveillance E, and End Results Program. ICD-O-3/WHO 2008, vol. 2023.

  2. Jung CK, Bychkov A, Kakudo K. Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach. Endocrinol Metab (Seoul). 2022;37:703–18.

    CAS  PubMed  Google Scholar 

  3. Chindris AM, Casler JD, Bernet VJ, Rivera M, Thomas C, Kachergus JM, et al. Clinical and molecular features of Hurthle cell carcinoma of the thyroid. J Clin Endocrinol Metab. 2015;100:55–62.

    CAS  PubMed  Google Scholar 

  4. Kushchayeva Y, Duh QY, Kebebew E, Clark OH. Prognostic indications for Hurthle cell cancer. World J Surg. 2004;28:1266–70.

    PubMed  Google Scholar 

  5. Coca-Pelaz A, Rodrigo JP, Shah JP, Sanabria A, Al Ghuzlan A, Silver CE, et al. Hurthle Cell Carcinoma of the Thyroid Gland: Systematic Review and Meta-analysis. Adv Ther. 2021;38:5144–64.

    PubMed  Google Scholar 

  6. Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer. 2005;103:1330–5.

    PubMed  Google Scholar 

  7. Nucera C. Evolution of resistance to thyroid cancer therapy. Aging (Albany NY). 2016;8:1576–7.

    PubMed  Google Scholar 

  8. Starenki D, Hong SK, Lloyd RV, Park JI. Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene. 2015;34:4624–34.

    CAS  PubMed  Google Scholar 

  9. Wu PK, Hong SK, Chen W, Becker AE, Gundry RL, Lin CW, et al. Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability. Sci Signal. 2020;13:eaay1478.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, et al. Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene. 2020;39:4257–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Starenki D, Sosonkina N, Hong SK, Lloyd RV, Park JI Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells. Int J Mol Sci 2019; 20.

  12. R2: Genomics Analysis and Visualization Platform

  13. Na Y, Kaul SC, Ryu J, Lee JS, Ahn HM, Kaul Z, et al. Stress chaperone mortalin contributes to epithelial-mesenchymal transition and cancer metastasis. Cancer Res. 2016;76:2754–65.

    CAS  PubMed  Google Scholar 

  14. Sun J, Che SL, Piao JJ, Xu M, Chen LY, Lin ZH. Mortalin overexpression predicts poor prognosis in early stage of non-small cell lung cancer. Tumour Biol. 2017;39:1010428317695918.

    PubMed  Google Scholar 

  15. Black JD, Rezvani K. Heat Shock Protein 70s as Potential Molecular Targets for Colon Cancer Therapeutics. Curr Med Chem. 2016;23:3171–88.

    CAS  PubMed  Google Scholar 

  16. Giguere V, Yang N, Segui P, Evans RM. Identification of a new class of steroid hormone receptors. Nature. 1988;331:91–4.

    CAS  PubMed  Google Scholar 

  17. Huss JM, Garbacz WG, Xie W. Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim Biophys Acta. 2015;1852:1912–27.

    CAS  PubMed  Google Scholar 

  18. Ao A, Wang H, Kamarajugadda S, Lu J. Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci USA. 2008;105:7821–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hamidian A, von Stedingk K, Munksgaard Thoren M, Mohlin S, Pahlman S. Differential regulation of HIF-1alpha and HIF-2alpha in neuroblastoma: Estrogen-related receptor alpha (ERRalpha) regulates HIF2A transcription and correlates to poor outcome. Biochem Biophys Res Commun. 2015;461:560–7.

    CAS  PubMed  Google Scholar 

  20. Cai Q, Lin T, Kamarajugadda S, Lu J. Regulation of glycolysis and the Warburg effect by estrogen-related receptors. Oncogene. 2013;32:2079–86.

    CAS  PubMed  Google Scholar 

  21. Chen Y, Zhang K, Li Y, He Q. Estrogen-related receptor alpha participates transforming growth factor-beta (TGF-beta) induced epithelial-mesenchymal transition of osteosarcoma cells. Cell Adh Migr. 2017;11:338–46.

    PubMed  Google Scholar 

  22. Dings MPG, van der Zalm AP, Bootsma S, van Maanen TFJ, Waasdorp C, van den Ende T, et al. Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer. Cell Rep Med. 2022;3:100802.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chang CY, Kazmin D, Jasper JS, Kunder R, Zuercher WJ, McDonnell DP. The metabolic regulator ERRalpha, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer. Cancer Cell. 2011;20:500–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Stein RA, Chang CY, Kazmin DA, Way J, Schroeder T, Wergin M, et al. Estrogen-related receptor alpha is critical for the growth of estrogen receptor-negative breast cancer. Cancer Res. 2008;68:8805–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Vernier M, McGuirk S, Dufour CR, Wan L, Audet-Walsh E, St-Pierre J, et al. Inhibition of DNMT1 and ERRalpha crosstalk suppresses breast cancer via derepression of IRF4. Oncogene. 2020;39:6406–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Vargas G, Bouchet M, Bouazza L, Reboul P, Boyault C, Gervais M, et al. ERRalpha promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. Oncogene. 2019;38:950–64.

    CAS  PubMed  Google Scholar 

  27. Kim S, Lee AJ, Yeo MK, Na YG, Kim JY, Cho MJ, et al. Clinicopathological Profiling of LC3B, an Autophagy Marker, and ESRRA (Estrogen-related Receptor-alpha) in Muscle-invasive Bladder Cancer. Anticancer Res. 2018;38:2429–37.

    CAS  PubMed  Google Scholar 

  28. Tiwari A, Swamy S, Gopinath KS, Kumar A. Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo. Sci Rep. 2015;5:17621.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu Z, Wang Y, Xiao ZG, Zou C, Zhang X, Wang Z, et al. Nuclear receptor ERRalpha and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer. Oncogene. 2018;37:6259–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.

    Google Scholar 

  32. Yoo SK, Lee S, Kim SJ, Jee HG, Kim BA, Cho H, et al. Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers. PLoS Genet. 2016;12:e1006239.

    PubMed  PubMed Central  Google Scholar 

  33. Yoo SK, Song YS, Lee EK, Hwang J, Kim HH, Jung G, et al. Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer. Nat Commun. 2019;10:2764.

    PubMed  PubMed Central  Google Scholar 

  34. Ganly I, Makarov V, Deraje S, Dong Y, Reznik E, Seshan V, et al. Integrated Genomic Analysis of Hurthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell. 2018;34:256–70.e255.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Giguere V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev. 2008;29:677–96.

    CAS  PubMed  Google Scholar 

  36. Rosen A, Casciola-Rosen L. Macromolecular substrates for the ICE-like proteases during apoptosis. J Cell Biochem. 1997;64:50–4.

    CAS  PubMed  Google Scholar 

  37. Busch BB, Stevens WC Jr, Martin R, Ordentlich P, Zhou S, Sapp DW, et al. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. J Med Chem. 2004;47:5593–6.

    CAS  PubMed  Google Scholar 

  38. Lanvin O, Bianco S, Kersual N, Chalbos D, Vanacker JM. Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790. J Biol Chem. 2007;282:28328–34.

    CAS  PubMed  Google Scholar 

  39. Li Y, Park JS, Deng JH, Bai Y. Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex. J Bioenerg Biomembr. 2006;38:283–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Laganiere J, Tremblay GB, Dufour CR, Giroux S, Rousseau F, Giguere V. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression. J Biol Chem. 2004;279:18504–10.

    CAS  PubMed  Google Scholar 

  41. Chaveroux C, Eichner LJ, Dufour CR, Shatnawi A, Khoutorsky A, Bourque G, et al. Molecular and genetic crosstalks between mTOR and ERRalpha are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab. 2013;17:586–98.

    CAS  PubMed  Google Scholar 

  42. Thomas-Chollier M, Hufton A, Heinig M, O’Keeffe S, Masri NE, Roider HG, et al. Transcription factor binding predictions using TRAP for the analysis of ChIP-seq data and regulatory SNPs. Nat Protoc. 2011;6:1860–9.

    CAS  PubMed  Google Scholar 

  43. Kim DK, Ryu D, Koh M, Lee MW, Lim D, Kim MJ, et al. Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is key regulator of hepatic gluconeogenesis. J Biol Chem. 2012;287:21628–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kraus RJ, Ariazi EA, Farrell ML, Mertz JE. Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. J Biol Chem. 2002;277:24826–34.

    CAS  PubMed  Google Scholar 

  45. Heckler MM, Thakor H, Schafer CC, Riggins RB. ERK/MAPK regulates ERRgamma expression, transcriptional activity and receptor-mediated tamoxifen resistance in ER+ breast cancer. FEBS J. 2014;281:2431–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bennett EP, Petersen BL, Johansen IE, Niu Y, Yang Z, Chamberlain CA, et al. INDEL detection, the ‘Achilles heel’ of precise genome editing: a survey of methods for accurate profiling of gene editing induced indels. Nucleic Acids Res. 2020;48:11958–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sahu A, Wang X, Munson P, Klomp JPG, Wang X, Gu SS, et al. Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha. Cancer Discov. 2023;13:672–701.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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:W90–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Xia H, Dufour CR, Giguere V. ERRalpha as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease. Front Endocrinol (Lausanne). 2019;10:206.

    PubMed  Google Scholar 

  50. Zielke A, Tezelman S, Jossart GH, Wong M, Siperstein AE, Duh QY, et al. Establishment of a highly differentiated thyroid cancer cell line of Hurthle cell origin. Thyroid. 1998;8:475–83.

    CAS  PubMed  Google Scholar 

  51. Mirebeau-Prunier D, Le Pennec S, Jacques C, Fontaine JF, Gueguen N, Boutet-Bouzamondo N, et al. Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One. 2013;8:e58683.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Patch RJ, Searle LL, Kim AJ, De D, Zhu X, Askari HB, et al. Identification of diaryl ether-based ligands for estrogen-related receptor alpha as potential antidiabetic agents. J Med Chem. 2011;54:788–808.

    CAS  PubMed  Google Scholar 

  53. Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017;144:2123–40.

    CAS  PubMed  Google Scholar 

  54. Wojakowska A, Chekan M, Marczak L, Polanski K, Lange D, Pietrowska M, et al. Detection of metabolites discriminating subtypes of thyroid cancer: Molecular profiling of FFPE samples using the GC/MS approach. Mol Cell Endocrinol. 2015;417:149–57.

    CAS  PubMed  Google Scholar 

  55. Nahm JH, Kim HM, Koo JS. Glycolysis-related protein expression in thyroid cancer. Tumour Biol. 2017;39:1010428317695922.

    PubMed  Google Scholar 

  56. Takacova M, Bullova P, Simko V, Skvarkova L, Poturnajova M, Feketeova L, et al. Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET-mediated activation of the HIF pathway. Am J Pathol. 2014;184:953–65.

    CAS  PubMed  Google Scholar 

  57. Lopez-Penabad L, Chiu AC, Hoff AO, Schultz P, Gaztambide S, Ordonez NG, et al. Prognostic factors in patients with Hurthle cell neoplasms of the thyroid. Cancer. 2003;97:1186–94.

    PubMed  Google Scholar 

  58. McFadden DG, Sadow PM. Genetics, Diagnosis, and Management of Hurthle Cell Thyroid Neoplasms. Front Endocrinol (Lausanne). 2021;12:696386.

    PubMed  Google Scholar 

  59. Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V, et al. Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res. 2006;66:6087–96.

    CAS  PubMed  Google Scholar 

  60. Gasparre G, Iommarini L, Porcelli AM, Lang M, Ferri GG, Kurelac I, et al. An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells. Hum Mutat. 2009;30:391–6.

    CAS  PubMed  Google Scholar 

  61. Baris O, Savagner F, Nasser V, Loriod B, Granjeaud S, Guyetant S, et al. Transcriptional profiling reveals coordinated up-regulation of oxidative metabolism genes in thyroid oncocytic tumors. J Clin Endocrinol Metab. 2004;89:994–1005.

    CAS  PubMed  Google Scholar 

  62. Savagner F, Mirebeau D, Jacques C, Guyetant S, Morgan C, Franc B, et al. PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma. Biochem Biophys Res Commun. 2003;310:779–84.

    CAS  PubMed  Google Scholar 

  63. Gopal RK, Vantaku VR, Panda A, Reimer B, Rath S, To TL, et al. Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hurthle Cell Carcinoma. Cancer Discov. 2023;13:1904–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Frank AR, Li V, Shelton SD, Kim J, Stott GM, Neckers LM, et al. Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hurthle Cell Carcinoma of the Thyroid. Cancer Discov. 2023;13:1884–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Odate T, Oishi N, Kawai M, Tahara I, Mochizuki K, Akaishi J, et al. Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation. Endocr Pathol. 2021;32:347–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ariazi EA, Kraus RJ, Farrell ML, Jordan VC, Mertz JE. Estrogen-related receptor alpha1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway. Mol Cancer Res. 2007;5:71–85.

    CAS  PubMed  Google Scholar 

  67. Deblois G, St-Pierre J, Giguere V. The PGC-1/ERR signaling axis in cancer. Oncogene. 2013;32:3483–90.

    CAS  PubMed  Google Scholar 

  68. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    CAS  PubMed  Google Scholar 

  69. Engstrom PG, Steijger T, Sipos B, Grant GR, Kahles A, Ratsch G, et al. Systematic evaluation of spliced alignment programs for RNA-seq data. Nat Methods. 2013;10:1185–91.

    PubMed  PubMed Central  Google Scholar 

  70. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:323.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–9.

    CAS  PubMed  Google Scholar 

  73. Breiman L. Random Forests. Machine Learning. 2001;45:5–32.

    Google Scholar 

  74. Song YS, Kim MJ, Sun HJ, Kim HH, Shin HS, Kim YA, et al. Aberrant Thyroid-Stimulating Hormone Receptor Signaling Increases VEGF-A and CXCL8 Secretion of Thyroid Cancer Cells, Contributing to Angiogenesis and Tumor Growth. Clin Cancer Res. 2019;25:414–25.

    CAS  PubMed  Google Scholar 

  75. Wu PK, Hong SK, Veeranki S, Karkhanis M, Starenki D, Plaza JA, et al. A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol. 2013;33:4051–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ichida M, Nemoto S, Finkel T. Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha). J Biol Chem. 2002;277:50991–5.

    CAS  PubMed  Google Scholar 

  77. Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20:1181–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Hong SK, Yoon S, Moelling C, Arthan D, Park JI. Noncatalytic function of ERK1/2 can promote Raf/MEK/ERK-mediated growth arrest signaling. J Biol Chem. 2009;284:33006–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Karkhanis M, Park JI. Sp1 regulates Raf/MEK/ERK-induced p21(CIP1) transcription in TP53-mutated cancer cells. Cell Signal. 2015;27:479–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Parker JB, Palchaudhuri S, Yin H, Wei J, Chakravarti D. A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function. Mol Cell Biol. 2012;32:1654–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tariq M, Saze H, Probst AV, Lichota J, Habu Y, Paszkowski J. Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin. Proc Natl Acad Sci USA. 2003;100:8823–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. proteinatlas.org HPA.

  84. Fisher FMaRA. Questions and Answers. The American Statistician. 1948;2:30–31.

    Google Scholar 

  85. Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 2019;47:W636–W641.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ. Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics. 2009;25:1189–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Fornes O, Castro-Mondragon JA, Khan A, van der Lee R, Zhang X, Richmond PA, et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2020;48:D87–D92.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Barry Nelkin (Johns Hopkins Medical Institute) for TPC1, BCPAP, FTC133, C643, 8505C, and TT; Dr. John A. Copland III (Mayo Clinic) for XTC.UC1; and Dr. Robert Gagel (MD Anderson) for MZ-CRC-1.

Funding

This work was supported by NIH/National Cancer Institute grants (R01CA138441 and R01CA269452) to J.P.

Author information

Author notes

  1. These authors contributed equally: Wenjing Chen, Young Shin Song.

Authors and Affiliations

  1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Wenjing Chen & Jong-In Park

  2. Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea

    Young Shin Song & Han Sai Lee

  3. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Young Shin Song, Han Sai Lee & Young Joo Park

  4. Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Chien-Wei Lin

  5. Department of Pathology, Konyang University School of Medicine, Daejeon, Republic of Korea

    Junguee Lee

  6. Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital & College of Medicine, Daejeon, Republic of Korea

    Yea Eun Kang

  7. Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    Seon-Kyu Kim

  8. Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    Seon-Young Kim

  9. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

    Young Joo Park

Authors
  1. Wenjing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young Shin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han Sai Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chien-Wei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junguee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yea Eun Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seon-Kyu Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Seon-Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Young Joo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jong-In Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, WC and JIP; methodology, WC, YSS, HSL, CWL, JL and JIP; formal analysis, WC, YSS, HSL, CWL, JL, YEK, SKK, SYK, and JIP; investigation, WC, YSS, HSL, CWL, JL and JIP; validation, WC, YSS, HSL and JIP; writing—original draft preparation, WC, YSS, and JIP; writing-review and editing, WC, YSS, YJP and JIP; visualization, WC, YSS, HSL, CWL, JL and JIP; supervision, YJP and JIP; project administration, JIP; funding acquisition, JIP. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Jong-In Park.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital (SNUH) and Medical College of Wisconsin (MCW) in accordance with the Declaration of Helsinki (approved ID: H-1108-041-372 and H-2303-179-1418). Written informed consent was obtained from each subject.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, W., Song, Y.S., Lee, H.S. et al. Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks. Oncogene 43, 2431–2446 (2024). https://doi.org/10.1038/s41388-024-03078-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03078-1

Search

Advanced search

Quick links