Too Much SP2 Protein Turns Stem Cells Into “Evil Twin” Tumor-forming Cancer Cells

Dr. Jon Horowitz, associate professor of molecular biomedical sciences, and a team of NC State researchers looked at the protein SP2, which regulates the activity of other genes.

They knew that elevated amounts of SP2 had been observed in human prostate-cancer patients, and that these levels only increased as the tumors became more dangerous. They then showed that precisely the same thing occurs in mouse skin tumors.

Horowitz and the team decided to look at SP2 as a possible cause of tumor formation in epithelial cell-derived tumors, which comprise about 80 percent of all human tumors; epithelial cells cover the body’s internal and external surfaces. They found that overproduction of the SP2 protein in epithelial stem cells stopped them from spawning mature descendants. The affected stem cells, unable to produce mature cells, just kept proliferating, resulting in the formation of tumors.

The researchers’ results are published in the Nov. 3 edition of the journal Cancer Research.

“Something happens to normal stem cells that changes the way SP2 is regulated, and it starts being overproduced,” Horowitz says. “SP2 basically hijacks the stem cell, and turns it into its evil twin – a cancer cell.”

Now that the link between tumor formation and SP2 has been shown, Horowitz says, scientists can turn their attention to looking at ways to target the overproduction of this protein. “Our hope is that we can find an ‘antidote’ to SP2, to restore normal cell proliferation to those cancer stem cells and reverse the process.”

The research was funded by a grant from the National Institutes of Health (NIH). The Department of Molecular Biomedical Sciences is part of NC State’s College of Veterinary Medicine.

Note to editors: Abstract of the paper follows.

“Overexpression of Transcription Factor Sp2 Inhibits Epidermal Differentiation and Increases Susceptibility to Wound and Carcinogen-Induced Tumorigenesis”
Authors: Tae-Hyung Kim, Shannon L. Chiera, Keith E. Linder, Robert C. Smart, and Jonathan M. Horowitz, NC State University; Carol S. Trempus, Metabolism and Molecular Mechanisms Group, Laboratory of Toxicology and Pharmacology, NIH, NIEHS

Published: Nov. 3 in Cancer Research

Abstract: Sp proteins are evolutionarily-conserved transcription factors required for the expression of a wide variety of genes that are critical for development and cell-cycle progression. De-regulated expression of certain Sp proteins is associated with the formation of a variety of human tumors, however direct evidence that any given Sp protein is oncogenic has been lacking. Here we report that Sp2 protein abundance in mice increases in concert with the progression of carcinogen-induced murine squamous cell carcinomas. Transgenic mice specifically overexpressing murine Sp2 in epidermal basal keratinocytes were highly susceptible to wound- and carcinogen-induced papillomagenesis. Transgenic animals that were homozygous rather than hemizygous for the Sp2 transgene exhibited a striking arrest in the epidermal differentiation program, perishing within two weeks of birth. Our results directly support the likelihood that Sp2 overexpression occurring in various human cancers has significant functional impact.