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Specificity Protein (Sp) Transcription Factors and Metformin Regulate Expression of the Long Non-coding RNA HULC
Gandhy, S., P. Imanirad, U. Jin, V. Nair, E. Hedrick, Y. Cheng, C. Corton, K. Kim, AND S. Safe. Specificity Protein (Sp) Transcription Factors and Metformin Regulate Expression of the Long Non-coding RNA HULC. ONCOGENE. MacMillan Magazines LIMITED, London, Uk, 6(28):26359-26372, (2015).
This paper contributes to the body of knowledge that epigenetic changes are an important determinant in cancer. In the present case this paper showed that a long non coding RNA can have profound effects on the behavior of liver cancer cells including key events in adverse outcome pathways such as cell proliferation, survival, and migration.
There is evidence that 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 up-regulated 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 demonstrated by RNAi showed that they play important roles in HCC cell proliferation, survival and migration. The relative contribution of Sp1, Sp3, Sp4 and HULC to 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 a negative 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 were observed in HepG2, SNU-449 and SK-Hep-1 cells treated with metformin which decreased expression of Sp TFs and HULC suggesting clinical applications of other antineoplastic agents that target Sp proteins for HCC chemotherapy.