Abstract
Signal transducer and activator of transcription STAT5 is an essential mediator of cytokine, growth factor and hormone signaling. While its activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated to a number of hematological and solid tumor cancers. We previously showed that deacetylase inhibitors can inhibit STAT5 transcriptional activity. We now investigated whether the dietary chemopreventive agent sulforaphane, known for its activity as deacetylase inhibitor, might also inhibit STAT5 activity and thus could act as a chemopreventive agent in STAT5-associated cancers. We describe here sulforaphane (SFN) as a novel STAT5 inhibitor. We showed that SFN, like the deacetylase inhibitor trichostatin A (TSA), can inhibit expression of STAT5 target genes in the B cell line Ba/F3, as well as in its transformed counterpart Ba/F3-1*6 and in the human leukemic cell line K562 both of which express a constitutively active form of STAT5. Similarly to TSA, SFN does not alter STAT5 initial activation by phosphorylation or binding to the promoter of specific target genes, in favor of a downstream transcriptional inhibitory effect. Chromatin immunoprecipitation assays revealed that, in contrast to TSA however, SFN only partially impaired the recruitment of RNA polymerase II at STAT5 target genes and did not alter histone H3 and H4 acetylation, suggesting an inhibitory mechanism distinct from that of TSA. Altogether, our data revealed that the natural compound sulforaphane can inhibit STAT5 downstream activity, and as such represents an attractive cancer chemoprotective agent targeting the STAT5 signaling pathway.
Highlights
With an estimated 32.6 million people living with cancer and 8.2 million deaths attributed to cancer worldwide in 2012 [1], cancer prevention has become a public health priority
We previously showed that the deacetylase inhibitors sodium butyrate, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) inhibit IL-3-mediated STAT5 transcriptional activity in the mouse pro-B cell line Ba/F3 [21]
Since we showed before that deacetylase inhibitors such as trichostatin A (TSA) can inhibit STAT5-mediated transcription [21], we investigated here whether SFN can inhibit STAT5 activity, possibly via inhibition of deacetylase activity
Summary
With an estimated 32.6 million people living with cancer and 8.2 million deaths attributed to cancer worldwide in 2012 [1], cancer prevention has become a public health priority. About a third of all cancer cases are thought to be associated to behavioral and dietary risks and are considered preventable [2,3]. Dietary chemoprevention has gained considerable interest over the past few years as a simple and efficient approach to lower overall cancer risk and reduce cancer incidence and mortality [2,3]. Since cancer is a multistep process from early carcinogenesis to tumor initiation, promotion and progression, the ability of the dietary molecule to target multiple pathways simultaneously would be advantageous. The isothiocyanate sulforaphane (SFN) found in abundance in cruciferous vegetables such as broccoli fulfill these requirements and is viewed as an ideal cancer chemopreventive agent [4,5,6]
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