Suppression of Spleen Tyrosine Kinase (Syk) by Histone Deacetylation Promotes, Whereas BAY61-3606, a Synthetic Syk Inhibitor Abrogates Colonocyte Apoptosis by ERK Activation.
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.
Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
Nirmalya
N
Dasgupta
Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
Bhupesh Kumar
BK
Thakur
Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
Atri
A
Ta
Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
Pujarini
P
Dutta
Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India.
Santasabuj
S
Das
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D003106:Colon / Q000166:cytology / Q000201:enzymology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D002087:Butyrates; D006657:Histones; D011743:Pyrimidines; D009536:Niacinamide; C000606896:SYK protein, human; D000072377:Syk Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006655:Histone Deacetylases
BAY61-3606; COLONOCYTE DIFFERENTIATION AND APOPTOSIS; COLORECTAL CANCER; HISTONE DEACETYLATION; SODIUM BUTYRATE; SPLEEN TYROSINE KINASE