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:

Thyroid transcription factor 1 enhances cellular statin sensitivity via perturbing cholesterol metabolism

Oncogene volume 37, pages 3290–3300 (2018)Cite this article

Subjects

Abstract

We have discovered an unexpected connection between a critical lung development and cancer gene termed thyroid transcription factor 1 (TTF-1 also known as NKX2-1) and cholesterol metabolism. Our published work implicates that TTF-1 positively regulates miR-33a which is known to repress ATP-binding cassette transporter 1 (ABCA1) and thus its cholesterol efflux activity. We set out to demonstrate that a higher TTF-1 expression would presumably inhibit cholesterol efflux and consequently raise intracellular cholesterol level. Surprisingly, raising TTF-1 expression actually lowers intracellular cholesterol level, which, we believe, is attributed to a direct transactivation of ABCA1 by TTF-1. Subsequently, we show that lung cancer cells primed with a TTF-1-driven decrease of cholesterol were more vulnerable to simvastatin, a frequently prescribed cholesterol biosynthesis inhibitor. In view of the fact that pathologists routinely interrogate human lung cancers for TTF-1 immunopositivity to guide diagnosis and the prevalent use of statins, TTF-1 should be further investigated as a putative biomarker of lung cancer vulnerability to statins.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, et al. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996;10:60–9.

    Article  CAS  PubMed  Google Scholar 

  2. Maeda Y, Dave V, Whitsett JA. Transcriptional control of lung morphogenesis. Physiol Rev. 2007;87:219–44.

    Article  CAS  PubMed  Google Scholar 

  3. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kendall J, Liu Q, Bakleh A, Krasnitz A, Nguyen KC, Lakshmi B, et al. Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer. Proc Natl Acad Sci USA. 2007;104:16663–8.

    Article  CAS  PubMed  Google Scholar 

  5. Kwei KA, Kim YH, Girard L, Kao J, Pacyna-Gengelbach M, Salari K, et al. Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer. Oncogene. 2008;27:3635–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tanaka H, Yanagisawa K, Shinjo K, Taguchi A, Maeno K, Tomida S, et al. Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 2007;67:6007–11.

    Article  CAS  PubMed  Google Scholar 

  7. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450:893–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473:101–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li CM, Gocheva V, Oudin MJ, Bhutkar A, Wang SY, Date SR, et al. Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes Dev. 2015;29:1850–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maeda Y, Tsuchiya T, Hao H, Tompkins DH, Xu Y, Mucenski ML, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Invest. 2012;122:4388–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol Cell. 2013;50:185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hosono Y, Yamaguchi T, Mizutani E, Yanagisawa K, Arima C, Tomida S, et al. MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis. EMBO J. 2012;31:481–93.

    Article  CAS  PubMed  Google Scholar 

  13. Phelps CA, Lai S-C, Mu D. Roles of thyroid transcription factor 1 in lung cancer biology. In: Litwack G(ed.) Vitamins and Hormones. London, UK: Elsevier; 2017. p. 517–44.

    Google Scholar 

  14. Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, et al. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. Genes Dev. 2013;27:197–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell. 2012;21:348–61.

    Article  CAS  PubMed  Google Scholar 

  16. Mu D. The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities. J Biol Chem. 2013;288:24992–5000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T. NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. Cancer Cell. 2013;23:718–23.

    Article  CAS  PubMed  Google Scholar 

  18. Runkle EA, Rice SJ, Qi J, Masser D, Antonetti DA, Winslow MM, et al. Occludin is a direct target of thyroid transcription factor-1 (TTF-1/NKX2-1). J Biol Chem. 2012;287:28790–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qi J, Rice SJ, Salzberg AC, Runkle EA, Liao J, Zander DS, et al. MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1. Cell Cycle. 2012;11:177–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rice SJ, Lai SC, Wood LW, Helsley KR, Runkle EA, Winslow MM, et al. MicroRNA-33a mediates the regulation of high mobility group AT-Hook 2 gene (HMGA2) by thyroid transcription factor 1 (TTF-1/NKX2-1). J Biol Chem. 2013;288:16348–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wood LW, Cox NI, Phelps CA, Lai SC, Poddar A, Talbot C Jr, et al. Thyroid transcription factor 1 reprograms angiogenic activities of secretome. Sci Rep. 2016;6:19857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fernandez-Hernando C, Suarez Y, Rayner KJ, Moore KJ. MicroRNAs in lipid metabolism. Curr Opin Lipidol. 2011;22:86–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;328:1566–69.

    Article  CAS  PubMed  Google Scholar 

  24. Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Clendening JW, Penn LZ. Targeting tumor cell metabolism with statins. Oncogene. 2012;31:4967–78.

    Article  CAS  PubMed  Google Scholar 

  26. Liu Z, Yanagisawa K, Griesing S, Iwai M, Kano K, Hotta N, et al. TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas. Oncogene. 2017;36:3740–48.

    Article  CAS  PubMed  Google Scholar 

  27. De Felice M, Damante G, Zannini M, Francis-Lang H, Di Lauro R. Redundant domains contribute to the transcriptional activity of the thyroid transcription factor 1. J Biol Chem. 1995;270:26649–56.

    Article  PubMed  Google Scholar 

  28. Oram JF, Lawn RM, Garvin MR, Wade DP. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem. 2000;275:34508–11.

    Article  CAS  PubMed  Google Scholar 

  29. Phillips MC. Molecular mechanisms of cellular cholesterol efflux. J Biol Chem. 2014;289:24020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pandyra A, Mullen PJ, Kalkat M, Yu R, Pong JT, Li Z, et al. Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Res. 2014;74:4772–82.

    Article  CAS  PubMed  Google Scholar 

  31. Long J, Basu Roy R, Zhang YJ, Antrobus R, Du Y, Smith DL, et al. Plasma membrane profiling reveals upregulation of ABCA1 by infected macrophages leading to restriction of mycobacterial growth. Front Microbiol. 2016;7:1086.

    PubMed  PubMed Central  Google Scholar 

  32. Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PI, Isanski BA, et al. 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. J Biol Chem. 2003;278:13244–56.

    Article  CAS  PubMed  Google Scholar 

  33. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem. 2000;275:28240–5.

    CAS  PubMed  Google Scholar 

  34. Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, et al. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999;104:R25–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen HW, Kandutsch AA, Waymouth C. Inhibition of cell growth by oxygenated derivatives of cholesterol. Nature. 1974;251:419–421.

    Article  CAS  PubMed  Google Scholar 

  37. Fernandez C, Martin M, Gomez-Coronado D, Lasuncion MA. Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression. J Lipid Res. 2005;46:920–9.

    Article  CAS  PubMed  Google Scholar 

  38. Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148:244–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014;19:393–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Besnard V, Xu Y, Whitsett JA. Sterol response element binding protein and thyroid transcription factor-1 (Nkx2.1) regulate Abca3 gene expression. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1395–1405.

    Article  CAS  PubMed  Google Scholar 

  41. Peca D, Cutrera R, Masotti A, Boldrini R, Danhaive O. ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. Biochem Soc Trans. 2015;43:913–9.

    Article  CAS  PubMed  Google Scholar 

  42. Oram JF, Lawn RM. ABCA1. The gatekeeper for eliminating excess tissue cholesterol. J Lipid Res. 2001;42:1173–1179.

    CAS  PubMed  Google Scholar 

  43. Smith B, Land H. Anticancer activity of the cholesterol exporter ABCA1gene. Cell Rep. 2012;2:580–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhao W, Prijic S, Urban BC, Tisza MJ, Zuo Y, Li L, et al. Candidate antimetastasis drugs suppress the metastatic capacity of breast cancer cells by reducing membrane fluidity. Cancer Res. 2016;76:2037–49.

    Article  CAS  PubMed  Google Scholar 

  45. Hafiane A, Genest J. ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis. Atherosclerosis. 2017;257:90–9.

    Article  CAS  PubMed  Google Scholar 

  46. Sharpe LJ, Brown AJ. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem. 2013;288:18707–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee BH, Taylor MG, Robinet P, Smith JD, Schweitzer J, Sehayek E, et al. Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1. Cancer Res. 2013;73:1211–8.

    Article  CAS  PubMed  Google Scholar 

  49. Flaveny CA, Griffett K, El-Gendy Bel D, Kazantzis M, Sengupta M, Amelio AL, et al. Broad anti-tumor activity of a small molecule that selectively targets the warburg effect and lipogenesis. Cancer Cell. 2015;28:42–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lin CY, Gustafsson JA. Targeting liver X receptors in cancer therapeutics. Nat Rev Cancer. 2015;15:216–24.

    Article  PubMed  Google Scholar 

  51. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6:1004–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149:515–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hornstein E, Shomron N. Canalization of development by microRNAs. Nat Genet. 2006;38:S20–4.

    Article  CAS  PubMed  Google Scholar 

  54. Li X, Cassidy JJ, Reinke CA, Fischboeck S, Carthew RW. A microRNA imparts robustness against environmental fluctuation during development. Cell. 2009;137:273–282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Allen RM, Marquart TJ, Albert CJ, Suchy FJ, Wang DQ, Ananthanarayanan M, et al. miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity. EMBO Mol Med. 2012;4:882–895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Arjun Poddar and Sohail Khan for assistance with bioinformatics and statistical analyses. This study was supported by the National Cancer Institute of the National Institutes of Health under Award Number R21CA198327. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Mu laboratory also acknowledges funding from the Fraternal Order of Eagles Aerie #4315, Colonial Beach, Virginia.

Author information

Author notes

  1. Shao-Chiang Lai

    Present address: bioAffinity Technologies Inc., San Antonio, TX, USA

  2. Sucharita M. Dutta

    Present address: Beth Israel Deaconess Medical School, Boston, MA, USA

Authors and Affiliations

  1. Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, 23501, USA

    Shao-Chiang Lai, Cody A. Phelps, Sucharita M. Dutta & David Mu

  2. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, 23501, USA

    Shao-Chiang Lai, Cody A. Phelps & David Mu

  3. Biotechnology Master’s Program, Eastern Virginia Medical School, Norfolk, VA, 23501, USA

    Aleena M. Short

Authors
  1. Shao-Chiang Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cody A. Phelps
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aleena M. Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sucharita M. Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Mu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lai, SC., Phelps, C.A., Short, A.M. et al. Thyroid transcription factor 1 enhances cellular statin sensitivity via perturbing cholesterol metabolism. Oncogene 37, 3290–3300 (2018). https://doi.org/10.1038/s41388-018-0174-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0174-7

This article is cited by

Search

Advanced search

Quick links