title: Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function.
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.
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Vito Giuseppe
authors.initials: VG
authors.lastname: D'Agostino
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Preet
authors.initials: P
authors.lastname: Lal
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mantelli
authors.affiliation: Department of Biochemistry, Hannover Medical University, Hannover, D-30625, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tiedje
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zucal
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Natthakan
authors.initials: N
authors.lastname: Thongon
authors.affiliation: Department of Biochemistry, Hannover Medical University, Hannover, D-30625, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Latorre
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, 80131, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Chemistry Department, University of Milan, Milan, 20133, Italy.
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.affiliation: Department of Drug Sciences, University of Pavia, Pavia, 27100, Italy.
authors.forename: Marialaura
authors.initials: M
authors.lastname: Amadio
authors.affiliation: Centre For Integrative Biology (CIBIO), University of Trento, Trento, 38123, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Provenzani
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005663:Furans; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D010616:Phenanthrenes / Q000494:pharmacology* / Q000633:toxicity; D011132:Polyribosomes / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011809:Quinones; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000067780:ELAV-Like Protein 1; D005663:Furans; D010616:Phenanthrenes; D011809:Quinones; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C000713095:dihydrotanshinone I