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

Oncogene. 2018 Jun;37(24):3290-3300. doi: 10.1038/s41388-018-0174-7. Epub 2018 Mar 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cholesterol / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • MicroRNAs / metabolism
  • Simvastatin / pharmacology
  • Thyroid Nuclear Factor 1 / genetics
  • Thyroid Nuclear Factor 1 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • DNA-Binding Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • MIRN33a microRNA, human
  • MicroRNAs
  • NKX2-1 protein, human
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Cholesterol
  • Simvastatin