Abstract
Epigenetic regulation of gene expression is an emerging target to treat several human diseases including cancers. In cancers, expressions of many tumor suppressor genes are suppressed by hyper-methylation in their regulatory regions. Herein, we describe a novel carbazole SH-I-14 that decreased the level of the acetyl-STAT3 at the K685 residue. Mutation analysis revealed that SH-I-14 disrupted STAT3-DNMT1 interaction by removing acetyl group from K685 of STAT3. Finally, the inhibition of STAT3-DNMT1 interaction by SH-I-14 resulted in re-expression of tumor suppressor genes such as VHL and PDLIM4 through de-methylation of their promoter regions. In addition, SH-I-14 showed anti-proliferative effect in triple-negative breast cancer (TNBC) cell lines in vitro and anti-tumor effect in a mouse xenograft model of MDA-MB-231 tumor. Taken together, our results suggest that targeting acetyl-STAT3 (K685) provides potential therapeutic opportunity to treat a subset of human cancers.
Highlights
Signal transducer and activator of transcription 3 (STAT3), a member of STAT family, is a transcriptional regulator that mediates transduction of extracellular signals to the nucleus in response to various cytokines [1]
SH-I-14 reduced phosphorylation of Y705 residue regardless of mutation at K685. These results suggest that disruption of STAT3DNMT1 interaction by SH-I-14 is dependent on the deacetylation of STAT3 at K685
It was observed that de-acetylation of STAT3 and expression of Von Hippel-Lindau tumor suppressor (VHL) and PDZ and LIM domain 4 (PDLIM4) was induced by SHI-14 in tumors from xenograft mice
Summary
Signal transducer and activator of transcription 3 (STAT3), a member of STAT family, is a transcriptional regulator that mediates transduction of extracellular signals to the nucleus in response to various cytokines [1]. STAT3 is widely recognized as a potential drug target because: a) activation and/or overexpression of STAT3 is widely associated with many human cancers [2,3,4]; b) it induces tumor-promoting inflammation and suppresses anti-tumor immunity [2]; and c) it induces various anti-apoptotic and/or pro-proliferative gene expressions [2]. STAT3 has been reported to have the repressive effects on the expression of tumor suppressor (TS) or pro-apoptotic genes [5,6,7,8,9,10,11]. It has been reported that STAT3 is regulated by multiple acetylation [12] and acetylation of STAT3 at K685 and is an important player in DNA methylation of promoter regions for TS genes through interaction with DNA (cytosine-5)-methyltransferase 1 (DNMT1) [13, 14]. Acetyl-STAT3 could be a potent target for tumor treatment and several smallwww.impactjournals.com/oncotarget molecules that inhibit the acetylation of -STAT3 have been reported [13, 15, 16]
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