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2015 ; 5
(ä): 16478
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Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its
post-transcriptional function
#MMPMID26553968
D'Agostino VG
; Lal P
; Mantelli B
; Tiedje C
; Zucal C
; Thongon N
; Gaestel M
; Latorre E
; Marinelli L
; Seneci P
; Amadio M
; Provenzani A
Sci Rep
2015[Nov]; 5
(ä): 16478
PMID26553968
show ga
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.