Oncotarget

Research Papers:

Disruption of STAT3-DNMT1 interaction by SH-I-14 induces re-expression of tumor suppressor genes and inhibits growth of triple-negative breast tumor

Hyo Jin Kang, Yong Weon Yi, Shu-Jie Hou, Hee Jeong Kim, Yali Kong, Insoo Bae and Milton L. Brown _

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Oncotarget. 2017; 8:83457-83468. https://doi.org/10.18632/oncotarget.4054

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Abstract

Hyo Jin Kang1,*, Yong Weon Yi1,*, Shu-Jie Hou1,3,*, Hee Jeong Kim1, Yali Kong1,3, Insoo Bae1,2,3,4 and Milton L. Brown1,3,4

1 Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

2 Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC, USA

3 Center for Drug Discovery, Georgetown University Medical Center, Washington, DC, USA

4 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

* These authors have contributed equally to this work

Correspondence to:

Milton L. Brown, email:

Keywords: SH-I-14, STAT3, DNMT1, acetylation, interaction

Received: February 05, 2015 Accepted: April 08, 2015 Published: May 09, 2015

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.


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