Butyrate suppresses Syk expression to promote colonocyte apoptosis

What is it about?

Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, regulates tumor progression, either negatively or positively, depending on the tissue lineage. Information about the role of Syk in colorectal cancers (CRC) is limited, and conflicting reports have been published. We studied Syk expression and its role in differentiation and apoptosis of the colonocytes. Here, we reported for the first time that expression of two transcript variants of Syk is suppressed in colonocytes during butyrate-induced differentiation, which mediates apoptosis of HT-29 cells. Despite being a known HDAC inhibitor, butyrate deacetylates histone3/4 around the transcription start site (TSS) of Syk. Histone deacetylation precludes the binding of RNA Polymerase II to the promoter and inhibits transcription. Since butyrate is a colonic metabolite derived from undigested fibers, our study offers a plausible explanation of the underlying mechanisms of the protective role of butyrate as well as the dietary fibers against CRC through the regulation of Syk. We also report that combined use of butyrate and highly specific Syk inhibitor BAY61-3606 does not enhance differentiation and apoptosis of colonocytes. Instead, BAY completely abolishes butyrate-induced differentiation and apoptosis in a Syk- and ERK1/2-dependent manner. While butyrate dephosphorylates ERK1/2 in HT-29 cells, BAY re-phosphorylates it, leading to its activation. This study describes a novel mechanism of butyrate action in CRC and explores the role of Syk in butyrate-induced differentiation and apoptosis. In addition, our study highlights those commercial small molecule inhibitors, although attractive drug candidates should be used with concern because of their frequent off-target effects.

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Why is it important?

we for the first time addressed the regulation of Syk expression during colonocyte differentiation. Our study shows that butyrate, despite its HDAC inhibitory role, augments promoter deacetylation to suppress Syk expression. We report that suppression of Syk mediates butyrate-induced apoptosis of the cells. Thus, our study reinforces the role of Syk as a pro-survival gene for colon carcinoma, at least in vitro. We reported an unusual function of BAY61-3606, which is known to be a highly specific Syk inhibitor. Instead of augmenting butyrate effects, BAY abrogated it by activating ERK1/2 pathway in a Syk-independent manner. Finally, this study expands our understanding of the role of Syk in CRC and explored additional mechanisms for the protective role of butyrate and dietary fibers against CRC.

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