Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
BMC Cancer. 2020 Feb 22;20(1):145. doi: 10.1186/s12885-020-6649-2.
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.
We used a combination of imaging, cell biological assays, and mouse xenografts to investigate the role of STAT3 in lung cancer development.
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.
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.
异常的 JAK/STAT 激活已在许多类型的人类癌症中被检测到。JAK/STAT 激活在癌症中的作用主要归因于磷酸化 STAT（pSTAT）对靶基因的直接转录调控，而未磷酸化的 STAT（uSTAT）则被认为处于休眠状态并位于细胞质中。然而，几项研究表明 uSTAT 可以在核内被发现。此外，已经表明，在小鼠中组织特异性缺失 STAT3 或 STAT5 会促进某些组织中的癌症生长，因此这些 STAT 蛋白可以作为肿瘤抑制因子。然而，迄今为止，尚未为 STAT 作为肿瘤抑制因子的功能显示出统一的机制。我们之前已经证明了果蝇 STAT 和人 STAT5A 的非典型 JAK/STAT 信号传导模式，其中一部分 uSTAT 位于核内并与异染色质蛋白 1（HP1）相关联；STAT 激活（通过磷酸化）导致其分散，导致 HP1 定位和异染色质丢失。
我们使用成像、细胞生物学测定和小鼠异种移植的组合来研究 STAT3 在肺癌发展中的作用。
我们发现 uSTAT3 在促进肺癌细胞异染色质形成、体外抑制细胞增殖和抑制小鼠异种移植肿瘤生长方面具有功能。
因此，uSTAT3 在促进异染色质形成中具有非典型功能，STAT3 的肿瘤抑制功能可能归因于非典型 JAK/STAT 途径中 uSTAT3 的异染色质促进活性。
