STAT3β: Not Such A Downer

STAT3 is a transcription factor that has been of particular interest to oncologists lately for its promotion of oncogenesis through constitutive activation. STAT3 has two key residues that must both by phosphorylated by a kinase in order for the protein to dimerize into a homodimer or heterodimer and thus be active. The two residues, tyrosine 705 and serine 727, are both found on exon 23. STAT3 is activated by several interferons, cytokines, and growth factors.

An article published in the October 25, 2011 edition of PNAS explored the study of Dr. Francesa Zammarchi et al on the alternative splicing that leads to two isoforms of STAT3: STAT3α and STAT3β. Exon 23, which includes the two amino acid residues necessary for activation of the STAT3 TF, can be fully or partially included in the final product. If the entire exon is included, STAT3α is formed and the protein is fully functional. If the 55 amino acids at the end of exon 23 are excluded from the final product, then STAT3β is made. The premature termination of the protein causes serine 727, a necessary residue for phosphorylation and activation of the STAT3 protein, to be truncated. This renders STAT3β able to maintain its DNA binding function, but not able to be fully active as a transcription factor.

Previously, it has been thought that STAT3β was a dominant-negative regulator based on its ability to bind DNA and thus competitively inhibit the activity of STAT3α. However, the findings of Zammarchi et al are questioning that designation, and have made a strong case for STAT3β as an antitumorigenic factor with its own specific set of regulated genes and proteins.

In a series of experiments that tested STAT3β regulation of both RNA and protein products, Zammarchi et al found that IL-8, LEGDF, and PCAF were all regulated specifically by STAT3β rather than total STAT3 knockdown. The transcription factor was demonstrated to downregulate both LEDGF and PCAF transcription and translation. IL-8 is involved in inflammation and in the chemotaxis of neutrophils, which are innate immune cells that phagocytose pathogens. LEDGF is a chromatin-binding protein and a transcriptional coactivator, as well as a pro-survival growth factor. PCAF is a histone acetyl transferase and transcriptional coactivator that promotes growth, invasion, and drug resistance. Clearly these genes are all of great interest to oncologists as potential cancer treatment targets, and thus STAT3β is coming into focus as a gene and protein of interest for all those involved in fighting cancer.

It has been previously demonstrated by Yue and Turkson1 that overexpression of STAT3β can induce apoptosis and inhibit tumor growth, and now the next step investigating the reasons for these effects has begun. Zammarchi et al showed that the STAT3β regulation occurs in several different types of cancer cell lines, including breast cancer, prostate cancer, and lung cancer, demonstrating the potential widespread nature of this factor as a cancer treatment target. There is still a long list of topics to be further investigated before STAT3β can be implicated as a prospective treatment target in humans including determining side effects, testing in animal models, and the development of drug delivery systems that are compatible with this substance, but nonetheless STAT3β appears to be a promising target for future oncological studies.

Reference:

Zammarchi, F. et al. (2011) Antitumorigenic potential of STAT3 alternative splicing modulation. PNAS 108(43):17779-84.

Additional Citation:

1) Yue, P., Turkson, J. (2009) Targeting STAT3 in cancer: How successful are we? Expert Opin Investig Drugs 18:45-56.