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The fungal natural product azaphilone-9 binds to HuR and inhibits HuR-RNA interaction in vitro

Kaur, Kawaljit
; 
Wu, Xiaoqing
; 
Fields, James K.
; 
Johnson, David K.
; 
Lan, Lan
; 
Pratt, Miranda
; 
Somoza, Amber D.
; 
Wang, Clay C. C.
; 
Karanicolas, John
; 
Oakley, Berl R.
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Abstract
The RNA-binding protein Hu antigen R (HuR) binds to AU-rich elements (ARE) in the 3’-untranslated region (UTR) of target mRNAs. The HuR-ARE interactions stabilize many oncogenic mRNAs that play important roles in tumorigenesis. Thus, small molecules that interfere with the HuR-ARE interaction could potentially inhibit cancer cell growth and progression. Using a fluorescence polarization (FP) competition assay, we identified the compound azaphilone-9 (AZA-9) derived from the fungal natural product asperbenzaldehyde, binds to HuR and inhibits HuR-ARE interaction (IC50 ~1.2 μM). Results from surface plasmon resonance (SPR) verified the direct binding of AZA-9 to HuR. NMR methods mapped the RNA-binding interface of HuR and identified the involvement of critical RNA-binding residues in binding of AZA-9. Computational docking was then used to propose a likely binding site for AZA-9 in the RNA-binding cleft of HuR. Our results show that AZA-9 blocks key RNA-binding residues of HuR and disrupts HuR-RNA interactions in vitro. This knowledge is needed in developing more potent AZA-9 derivatives that could lead to new cancer therapy.
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Date
2017-04-17
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Public Library of Science
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Molecular Biosciences Scholarly Works
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Kaur K, Wu X, Fields JK, Johnson DK, Lan L, Pratt M, et al. (2017) The fungal natural product azaphilone-9 binds to HuR and inhibits HuR-R NA interaction in vitro. PLoS ONE 12(4): e0175471. https://doi.org/10.1371/journal.pone.0175471
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https://hdl.handle.net/1808/27352
DOI
10.1371/journal.pone.0175471
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