Abstract
BackgroundWe recently reported that STAT1 plays a tumor suppressor role, and ERK was inversely correlation with STAT1 expression in esophageal squamous cell carcinoma (ESCC). Here, we investigated the mechanism(s) that are responsible for the ERK regulates STAT1 in ESCC.MethodsWe performed the immunoprecipitation (IP) to detect the ubiquitin of STAT1 upon MEK transfection or U0126 treatment and co-IP to confirm the binding of STAT1 and ERK in ESCC cell lines.ResultsWe found evidence that the ubiquitin-proteasome pathway can efficiently degrade STAT1 in ESCC cells, as MG132 treatment rapidly and dramatically increased STAT1 expression in these cells. This process is not dependent on the phosphorylation of the two important STAT1 residues, Y701 and S727, as site-directed mutagenesis of these two sites did not affect STAT1 degradation. We also found that ERK promotes proteasome degradation of STAT1, supported by the observations that pharmacologic inhibition of ERK resulted in a substantial increase of STAT1 whereas expression of constitutively active ERK further reduced the STAT1 protein level. In addition to suppressing STAT1 expression, ERK limited STAT1 signaling by decreasing the production of IFNγ.ConclusionTo conclude, ERK is an effective negative regulator of STAT1 signaling in ESCC, by promoting its proteasome degradation and decreasing IFNγ production. Our data further supports that targeting ERK and/or STAT1 may be useful for treating ESCC.
Highlights
We recently reported that STAT1 plays a tumor suppressor role, and Extracellular regulated protein kinases (ERK) was inversely correlation with STAT1 expression in esophageal squamous cell carcinoma (ESCC)
MG132 increases the protein expression of STAT1 in ESCC cell lines To investigate the mechanism(s) by which STAT1 is down-regulated in ESCC, we questioned if the STAT1 gene is silenced via gene methylation
By Western blots and quantitative RT-PCR, we did not find any appreciable change in STAT1 nor phospho(p)-STAT1 expression, suggesting that gene methylation does not play a role in suppressing STAT1 expression in ESCC (Additional file 1: Figure S1)
Summary
We recently reported that STAT1 plays a tumor suppressor role, and ERK was inversely correlation with STAT1 expression in esophageal squamous cell carcinoma (ESCC). We investigated the mechanism(s) that are responsible for the ERK regulates STAT1 in ESCC. Esophageal squamous cell carcinoma (ESCC) is one of the leading cancer worldwide, especially China [1]. The growth of ESCC is regulated via a complex network of signal transduction pathways. The JAK-STAT (Signal transducers and activators of transcription) signaling pathway has been identified as a potential target for novel cancer therapies. STAT1 is a critical mediator of cytokine signaling [3]. STAT1 is a key mediator in gamma-interferon (IFNγ) signaling, which activates STAT1 by its phosphorylation. STAT1 has been reported as a tumor suppressor in breast cancer, multiple myeloma and
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