Research Papers:

Specificity protein (Sp) transcription factors and metformin regulate expression of the long non-coding RNA HULC

Shruti U. Gandhy, Parisa Imanirad, Un-Ho Jin, Vijayalekshmi Nair, Eric Hedrick, Yating Cheng, Christopher J. Corton, KyoungHyun Kim and Stephen Safe _

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Oncotarget. 2015; 6:26359-26372. https://doi.org/10.18632/oncotarget.4560

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Shruti U. Gandhy1,*, Parisa Imanirad2,*, Un-Ho Jin1,*, Vijayalekshmi Nair2,*, Eric Hedrick2,*, Yating Cheng2, J. Christopher Corton3, KyoungHyun Kim4, Stephen Safe1,2

1Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, TX, USA

2Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA

3Integrated Systems Toxicology Division, US-EPA, MD B143-06, Research Triangle Park, NC, USA

4Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA

*These authors have contributed equally to this work

Correspondence to:

Stephen Safe, e-mail: [email protected]

Keywords: HCC, Sp proteins, HULC, IncRNAs

Received: May 19, 2015     Accepted: June 23, 2015     Published: July 06, 2015


Specificity protein 1 (Sp1) transcription factor (TF) regulates expression of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) cells. RNA interference (RNAi) studies showed that among several lncRNAs expressed in HepG2, SNU-449 and SK-Hep-1 cells, highly upregulated in liver cancer (HULC) was regulated not only by Sp1 but also Sp3 and Sp4 in the three cell lines. Knockdown of Sp transcription factors and HULC by RNAi showed that they play important roles in HCC cell proliferation, survival and migration. The relative contribution of Sp1, Sp3, Sp4 and HULC on these responses in HepG2, SNU-449 and SK-Hep-1 cells were cell context- and response-dependent. In the poorly differentiated SK-Hep-1 cells, knockdown of Sp1 or HULC resulted in genomic and morphological changes, indicating that Sp1 and Sp1-regulated HULC are important for maintaining the mesenchymal phenotype in this cell line. Genomic analysis showed an inverse correlation between expression of genes after knockdown of HULC and expression of those genes in liver tumors from patients. The antidiabetic drug metformin down-regulates Sp proteins in pancreatic cancer, and similar results including decreased HULC expression were observed in HepG2, SNU-449 and SK-Hep-1 cells treated with metformin, indicating that metformin and other antineoplastic agents that target Sp proteins may have clinical applications for HCC chemotherapy.

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