Signaling Protein Stabilizes Heterochromatin and Suppresses Tumor Growth

Disruption of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system, and play a role in maintaining immune tolerance and tumor surveillance. STAT5A is activated by and it mediates the responses of many cell ligands, such as interleukins and growth hormones.

Investigators at the University of California, San Diego School of Medicine (USA; www.ucsd.edu) and their colleagues at the University of Rochester Medical Center (NY, USA) worked with a mouse xenograft colon cancer model to study the effects of STAT5A.

They reported in the June 3, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that unphosphorylated STAT5A bound to the heterochromatin protein 1-alpha (HP1-alpha) and stabilized the heterochromatin. Expressing unphosphorylated STAT5A or HP1-alpha inhibited colon cancer growth in the mouse xenograft model.

Previous experiments conducted in fruit flies had shown that the unphosphorylated form of STAT5A caused chromatin to condense into heterochromatin, while the phosphorylated form prompted dispersal and loss of heterochromatin, furthering gene expression.

“Unphosphorylated STAT promotes and stabilizes heterochromatin formation, which in turn suppresses gene transcription,” said senior author Dr. Willis X. Li, professor of medicine at the University of California, San Diego School of Medicine. “When we expressed either HP1-alpha (the central component of heterochromatin) or unphosphorylated STAT5A in human cancer cells, many genes important for cancer growth are suppressed. These cancer cells do not grow as fast or big as their control parental cancer cells in mouse xenograft models.”

Transcriptome profiling showed that expressing unphosphorylatable STAT5A had similar effects to overexpressing HP1-alpha in global gene expression. The majority of the genes commonly repressed by unphosphorylated STAT5A and HP1-alpha have been implicated in cancer development, and down regulation, somatic mutations, and deletions of STAT5 genes are found in certain human cancers.

“We are in the process of identifying small molecule drugs that may promote heterochromatin formation without stopping cell division or causing cell death,” said Dr. Li. “These drugs, if found, may be effective in treating cancers with fewer side effects.”

Related Links:
University of California, San Diego School of Medicine
University of Rochester Medical Center