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Suppression of Spleen Tyrosine Kinase (Syk) by Histone Deacetylation Promotes, Whereas BAY61‐3606, a Synthetic Syk Inhibitor Abrogates Colonocyte Apoptosis by ERK Activation
Author(s) -
Dasgupta Nirmalya,
Thakur Bhupesh Kumar,
Ta Atri,
Dutta Pujarini,
Das Santasabuj
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25625
Subject(s) - syk , butyrate , cancer research , apoptosis , chemistry , microbiology and biotechnology , tyrosine kinase , histone , kinase , histone h3 , biology , signal transduction , biochemistry , gene , fermentation
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. J. Cell. Biochem. 118: 191–203, 2017. © 2016 Wiley Periodicals, Inc.