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

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.

Mechanistic Study of TTF-1 Modulation of Cellular Sensitivity to Cisplatin

“…6 reporting that the rat Ttf-1 transgene sensitizes the TTF-1 − human lung AD cell line A549 to cisplatin, we investigated how the human TTF-1 would impact cisplatin sensitivity of A549 cells. The expression of the TTF-1 transgene in A549-TTF-1 cells was documented by immunoblotting and RT-QPCR in our published studies 24,25 . TTF-1 -transfectant cells and a control - the empty vector (EV) transfectant cells – were treated with cisplatin for 48 hr (Fig.…”

“…Although TTF-1 is a transcription factor that is not directly druggable by small molecules, studies such as the present one may shed new light on exploiting TTF-1 to improve lung cancer management. Case in point is our recent work which has identified TTF-1 as a putative indicator of lung cancer vulnerability to statins 24 .…”

Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies

“…MED27 (mediator complex subunit) is involved in gene expression regulation and required for activity of the enhancer binding protein SP1. TTF1 (transcription termination factor) enhances cellular statin sensitivity via perturbing cholesterol metabolism [43]. Significant eQTL associations occurred with SNPs of NTNG2, LINC01314 and DCLK2 with expression in skeletal muscle, heart and/or whole blood.…”

Сучасне Уявлення Про Синдром «мозок — Легені — Щитоподібна Залоза» Та Його Легеневі Прояви

“…В связи с обнаружением взаимосвязи между нарушением онтогенеза легких, фактором транскрипции щитовидной железы 1 (TTF-1, также известным как NKX2-1) и метаболизмом холестерина через позитивную регуляцию miR-33a, который, как известно, подавляет ATP-связывающий кассетный транспортер 1 (ABCA1), открываются перспективы лечения рака легких статинами [15].…”