A Novel Small Molecule Activator of Nuclear Receptor SHP Inhibits HCC Cell Migration via Suppressing Ccl2.

Mol Cancer Ther
Authors
Abstract

Small heterodimer partner (SHP, NR0B2) is a nuclear orphan receptor without endogenous ligands. Due to its crucial inhibitory role in liver cancer, it is of importance to identify small molecule agonists of SHP. As such, we initiated a probe discovery effort to identify compounds capable of modulating SHP function. First, we performed binding assays using small molecule microarrays (SMM) and discovered 5-(diethylsulfamoyl)-3-hydroxynaphthalene-2-carboxylic acid (DSHN) as a novel activator of SHP. DSHN transcriptionally activated Shp mRNA, but also stabilized the SHP protein by preventing its ubiquitination and degradation. Second, we identified Ccl2 as a new SHP target gene by RNA-seq. We showed that activation of SHP by DSHN repressed Ccl2 expression and secretion by inhibiting p65 activation of CCL2 promoter activity, as demonstrated in vivo in Shp(-/-) mice and in vitro in HCC cells with SHP overexpression and knockdown. Third, we elucidated a strong inhibitory effect of SHP and DSHN on HCC cell migration and invasion by antagonizing the effect of CCL2. Lastly, by interrogating a publicly available database to retrieve SHP expression profiles from multiple types of human cancers, we established a negative association of SHP expression with human cancer metastasis and patient survival. In summary, the discovery of a novel small molecule activator of SHP provides a therapeutic perspective for future translational and preclinical studies to inhibit HCC metastasis by blocking Ccl2 signaling. Mol Cancer Ther; 15(10); 2294-301. ©2016 AACR.

Year of Publication
2016
Journal
Mol Cancer Ther
Volume
15
Issue
10
Pages
2294-2301
Date Published
2016 Oct
ISSN
1538-8514
DOI
10.1158/1535-7163.MCT-16-0153
PubMed ID
27486225
PubMed Central ID
PMC5050121
Links
Grant list
R21 AA022482 / AA / NIAAA NIH HHS / United States
R01 DK080440 / DK / NIDDK NIH HHS / United States
I01 BX002634 / BX / BLRD VA / United States
R01 DK104656 / DK / NIDDK NIH HHS / United States
R01 CA160860 / CA / NCI NIH HHS / United States
P30 DK034989 / DK / NIDDK NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
R01 ES025909 / ES / NIEHS NIH HHS / United States