Unphosphorylated STAT3 in heterochromatin formation and tumor suppression in lung cancer

Pranabananda Dutta,Yuanlin Song,Yingxiao Wang,Jinghong Li,Phillippe R Montgrain,Qin Peng,Willis X Li,Lin Zhang,Huijun Zhang

doi:10.1186/s12885-020-6649-2

Abstract

BackgroundAberrant 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.MethodsWe used a combination of imaging, cell biological assays, and mouse xenografts to investigate the role of STAT3 in lung cancer development.ResultsWe 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.ConclusionsThus, 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.

Highlights

Aberrant Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) activation has been detected in many types of human cancers
We found that STAT3 and HP1α partially colocalize in the nucleus and might physically interact, and that uSTAT3 promotes heterochromatin formation and suppresses lung cancer cell proliferation in vitro and in vivo
We found high fluorescence resonance energy transfer (FRET) efficiency from anti-HP1α-Alexa488 to antiSTAT3-Alexa546 only in discrete regions of the nucleus (Fig. 1c), suggesting that STAT3 and HP1α physically interact in these regions of the nucleus

Summary

Introduction

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. 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. 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. 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 [9,10,11,12,13,14,15,16]. It has been shown that STAT3 maintains a prominent nuclear presence independent of its tyrosine phosphorylation status in several mammalian cell lines [12, 13, 16], and that

Methods

Results

Discussion

Conclusion