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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\u2010induced differentiation, which mediates apoptosis of HT\u201029 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\u20103606 does not enhance differentiation and apoptosis of colonocytes. Instead, BAY completely abolishes butyrate\u2010induced differentiation and apoptosis in a Syk\u2010 and ERK1\/2\u2010dependent manner. While butyrate dephosphorylates ERK1\/2 in HT\u201029 cells, BAY re\u2010phosphorylates it, leading to its activation. This study describes a novel mechanism of butyrate action in CRC and explores the role of Syk in butyrate\u2010induced 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\u2010target effects. J. Cell. Biochem. 118: 191\u2013203, 2017. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcb.25625","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T11:53:59Z","timestamp":1465818839000},"page":"191-203","source":"Crossref","is-referenced-by-count":10,"title":["Suppression of Spleen Tyrosine Kinase (Syk) by Histone Deacetylation Promotes, Whereas BAY61\u20103606, a Synthetic Syk Inhibitor Abrogates Colonocyte Apoptosis by ERK Activation"],"prefix":"10.1002","volume":"118","author":[{"given":"Nirmalya","family":"Dasgupta","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine National Institute of Cholera and Enteric Diseases P\u201033, C.I.T. 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