It has been shown that uSTAT5 in the nucleus directly binds to and represses differentiation genes in hematopoietic progenitor cells. In addition, uSTAT5A physically interacts with HP1α via an HP1-binding motif, PxVxI, present in STAT proteins. This observation is consistent with reports by other groups (see Fig. We have shown that both endogenous STAT5A and transfected uSTAT5A (or STAT5A Y694F) are prominently present in the nucleus of cultured human cells. Our previous work has shown that the STAT-HP1 interaction is mechanistically and functionally conserved in human cells for STAT5A, which is most homologous to Drosophila STAT92E. Further, uSTAT1, 3, and 5 can bind to DNA and to regulate gene transcription. Specifically, it has been shown that STAT3 maintains a prominent nuclear presence independent of its tyrosine phosphorylation status in several mammalian cell lines, and that uSTAT5 similarly is detected in the nucleus of serum-starved unstimulated cells, where STATs are not phosphorylated.
Many groups have reported that uSTATs can translocate into and prominently exist in the nucleus in various mammalian cells at quiescence, when STAT proteins are not phosphorylated.
Other groups have shown that human JAK2 activation reduces heterochromatin in leukemia and stem cells. JAK activation can increase pSTAT and decrease uSTAT, thus causing heterochromatin instability. However, our previously research using Drosophila STAT92E and human STAT5A has demonstrated a non-canonical JAK/STAT signaling, in which uSTAT is capable of associating with HP1 and stabilizing heterochromatin. In the canonical JAK/STAT signaling pathway, activated JAK phosphorylates STAT at a tyrosine residue around a.a.700, and the resulting phosphorylated STAT (pSTAT) dimerizes and translocates to the nucleus, where it functions as a transcription factor, while the dormant unphosphorylated STAT (uSTAT) in the cytoplasm has no significant functions. Thus, uSTAT3 possesses noncanonical function in promoting heterochromatin formation, and the tumor suppressor function of STAT3 is likely attributable to the heterochromatin-promoting activity of uSTAT3 in the non-canonical JAK/STAT pathway.
We found that uSTAT3 has a function in promoting heterochromatin formation in lung cancer cells, suppressing cell proliferation in vitro, and suppressing tumor growth in mouse xenografts. We used a combination of imaging, cell biological assays, and mouse xenografts to investigate the role of STAT3 in lung cancer development. We have previously demonstrated a non-canonical mode of JAK/STAT signaling for Drosophila STAT and human STAT5A, where a fraction of uSTAT is in the nucleus and associated with Heterochromatin Protein 1 (HP1) STAT activation (by phosphorylation) causes its dispersal, leading to HP1 delocalization and heterochromatin loss. However, no unifying mechanism has been shown for the tumor suppressor function of STATs to date. In addition, it has been shown that tissue-specific loss of STAT3 or STAT5 in mice promotes cancer growth in certain tissues, and thus these STAT proteins can act as tumor suppressors. However, several studies have shown that uSTATs can be found in the nucleus. The role of JAK/STAT activation in cancer has been mostly attributed to direct transcriptional regulation of target genes by phosphorylated STAT (pSTAT), while the unphosphorylated STAT (uSTAT) is believed to be dormant and reside in the cytoplasm. Aberrant JAK/STAT activation has been detected in many types of human cancers.