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Dihydrotanshinone-I Interferes With the RNA-binding Activity of HuR Affecting Its Post-Transcriptional Function

Dihydrotanshinone-I Interferes With the RNA-binding Activity of HuR Affecting Its Post-Transcriptional Function

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

Sci Rep. 2015 Nov 10;5:16478.

PMID: 26553968

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP87205990	Dihydrotanshinone I		87205-99-0	Price

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