Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function

作者：D'Agostino Vito Giuseppe; Lal Preet; Mantelli Barbara; Tiedje Christopher; Zucal Chiara; Thongon Natthakan; Gaestel Matthias; Latorre Elisa; Marinelli Luciana; Seneci Pierfausto; Amadio Marialaura; Provenzani Alessandro^*

来源：Scientific Reports, 2015, 5(1): 16478.

DOI：10.1038/srep16478

Post-transcriptional regulation is an essential determinant of gene expression programs in physiological and pathological conditions. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs, critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). We identified the low molecular weight compound 15,16-dihydrotanshinone-I (DHTS), well known in traditional Chinese medicine practice, through a validated high throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR: RNA complex formation. We found that DHTS interferes with the association step between HuR and the RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki = 3.74 +/- 1.63 nM). In breast cancer cell lines, short term exposure to DHTS influences mRNA stability and translational efficiency of TNF in a HuR-dependent manner and also other functional readouts of its post-transcriptional control, such as the stability of selected pre-mRNAs. Importantly, we show that migration and sensitivity of breast cancer cells to DHTS are modulated by HuR expression, indicating that HuR is among the preferential intracellular targets of DHTS. Here, we disclose a previously unrecognized molecular mechanism exerted by DHTS, opening new perspectives to therapeutically target the HuR mediated, post-transcriptional control in inflammation and cancer cells.

• 出版日期2015-11-10