Unphosphorylated STAT3 in heterochromatin formation and tumor suppression in lung cancer

Abstract

Background: Aberrant JAK/STAT activation has been detected in many types of human cancers. 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. However, several studies have shown that uSTATs can be found in the nucleus. 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, no unifying mechanism has been shown for the tumor suppressor function of STATs to date. 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. Methods: We used a combination of imaging, cell biological assays, and mouse xenografts to investigate the role of STAT3 in lung cancer development. Results: 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. Conclusions: 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.

Aging mechanisms—A perspective mostly from Drosophila

“…It was demonstrated that a JAK downstream transcription factor, the signal‐transducer and activator of transcription protein at 92E (Stat92E), in its unphosphorylated form, interacts with HP1a, promoted heterochromatin formation, 92,96,97 and enhanced genome stability 98 ; moreover, this interaction was also found to protect against leukemia‐like cancer formation 92 . A similar mechanism was also demonstrated in mammals to suppress cancer development, 99,100 highlighting the advantage of using Drosophila for discovering conserved mechanisms.…”

“…• Reduced expression of NuRD components in Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670), HGPS-derived cells and those from older donors • Reduced HDAC1 activity (encoded by Hsa-HDAC1) was also found (the NuRD chromatin remodeling complex that includes HDAC1 and HDAC2), suggesting that the mechanism could also be related to histone acetylation [296] mechanism was also demonstrated in mammals to suppress cancer development, 99,100 highlighting the advantage of using Drosophila for discovering conserved mechanisms.…”

Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing

“…To identify potential mechanisms by which senescent cells impact on alveolar epithelial cells modulation of known SASP factors such as IL-6, IL-1β, PDGF, FGFb, PGE 2 and ROS would be the focus of future studies [41,42]. Interestingly, STAT3 has been reported to be involved in fibroblast senescence but a recent publication has highlighted the potential involvement in epithelial cell senescence [43]. This is the first study to show that senescent LFs are able to reduce alveolar epithelial cell proliferation in a co-culture system.…”

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases

“…Indeed, not only has STAT3 been linked to fibrosis in the liver but it is also an important regulator in a model of oxidative stress-induced senescence in primary human lung fibroblasts [ 41 ]. Recently, it was suggested that STAT3 potentially is involved in epithelial cell senescence [ 106 ]. In addition to regulation by TGF-β, it was concluded that matrix stiffness has a substantial impact on the intrinsic and extrinsic activation of the STAT3 pathway in hepatocellular carcinoma cells [ 107 ].…”