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Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling.

Xiong H, Chen ZF, Liang QC, Du W, Chen HM, Su WY, Chen GQ, Han ZG, Fang JY - J. Cell. Mol. Med. (2009)

Bottom Line: Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling.Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells.Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China.

ABSTRACT
DNA methyltransferase inhibitors (MTIs) have recently emerged as promising chemotherapeutic or preventive agents for cancer, despite their poorly characterized mechanisms of action. The present study shows that DNA methylation is integral to the regulation of SH2-containing protein tyrosine phosphatase 1 (SHP1) expression, but not for regulation of suppressors of cytokine signalling (SOCS)1 or SOCS3 in colorectal cancer (CRC) cells. SHP1 expression correlates with down-regulation of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3/STAT5) signalling, which is mediated in part by tyrosine dephosphorylation events and modulation of the proteasome pathway. Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling. We demonstrate that 5-aza-dc suppresses growth of CRC cells, and induces G2 cell cycle arrest and apoptosis through regulation of downstream targets of JAK2/STAT3/STAT5 signalling including Bcl-2, p16(ink4a), p21(waf1/cip1) and p27(kip1). Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells. Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling. This study represents the first evidence towards establishing a mechanistic link between inhibition of JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells that may lead to the use of MTIs as a therapeutic intervention for human colorectal cancer.

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The possible mechanistic link between JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells. Using an inhibitor of DNA methytransferase, 5-aza-dc, methylation was shown to be integral to the regulation of SHP1 expression, and SHP1 appears to down-regulate JAK2 by two mechanisms: tyrosine dephosphorylation and the proteasome pathway. The decrease in STAT3 expression observed in CRC cells exposed to 5-aza-dc is unclear at this point and requires additional study, while STAT5 appears to be unaffected by an inhibition of methylation.
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fig08: The possible mechanistic link between JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells. Using an inhibitor of DNA methytransferase, 5-aza-dc, methylation was shown to be integral to the regulation of SHP1 expression, and SHP1 appears to down-regulate JAK2 by two mechanisms: tyrosine dephosphorylation and the proteasome pathway. The decrease in STAT3 expression observed in CRC cells exposed to 5-aza-dc is unclear at this point and requires additional study, while STAT5 appears to be unaffected by an inhibition of methylation.

Mentions: In summary, the present study is the first to demonstrate that JAK2/STAT3/STAT5 signalling has a role in MTI-induced cell growth arrest, apoptosis and invasion in human CRC cells. We determined that DNA methylation is integral to regulation of SHP1 expression, and 5-aza-dc-induced up-regulation of SHP1 expression correlates with significant down-regulation of JAK2/STAT3/STAT5 signalling in CRC cells. Based on these data, we suggest that DNA methylase inhibition is a mechanism by which inhibition of JAK2/STAT3/STAT5 signalling can occur in CRC cells (Fig. 8). Therefore, further study of 5-aza-dc on JAK2/STAT3/STAT5 signalling in CRC tumorigenesis and progression has the potential to advance the development of effective agents for CRC prevention and therapy. Additionally, since 5-aza-dc also affects mRNA stability, further studies regarding this effect should be performed.


Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling.

Xiong H, Chen ZF, Liang QC, Du W, Chen HM, Su WY, Chen GQ, Han ZG, Fang JY - J. Cell. Mol. Med. (2009)

The possible mechanistic link between JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells. Using an inhibitor of DNA methytransferase, 5-aza-dc, methylation was shown to be integral to the regulation of SHP1 expression, and SHP1 appears to down-regulate JAK2 by two mechanisms: tyrosine dephosphorylation and the proteasome pathway. The decrease in STAT3 expression observed in CRC cells exposed to 5-aza-dc is unclear at this point and requires additional study, while STAT5 appears to be unaffected by an inhibition of methylation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4516515&req=5

fig08: The possible mechanistic link between JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells. Using an inhibitor of DNA methytransferase, 5-aza-dc, methylation was shown to be integral to the regulation of SHP1 expression, and SHP1 appears to down-regulate JAK2 by two mechanisms: tyrosine dephosphorylation and the proteasome pathway. The decrease in STAT3 expression observed in CRC cells exposed to 5-aza-dc is unclear at this point and requires additional study, while STAT5 appears to be unaffected by an inhibition of methylation.
Mentions: In summary, the present study is the first to demonstrate that JAK2/STAT3/STAT5 signalling has a role in MTI-induced cell growth arrest, apoptosis and invasion in human CRC cells. We determined that DNA methylation is integral to regulation of SHP1 expression, and 5-aza-dc-induced up-regulation of SHP1 expression correlates with significant down-regulation of JAK2/STAT3/STAT5 signalling in CRC cells. Based on these data, we suggest that DNA methylase inhibition is a mechanism by which inhibition of JAK2/STAT3/STAT5 signalling can occur in CRC cells (Fig. 8). Therefore, further study of 5-aza-dc on JAK2/STAT3/STAT5 signalling in CRC tumorigenesis and progression has the potential to advance the development of effective agents for CRC prevention and therapy. Additionally, since 5-aza-dc also affects mRNA stability, further studies regarding this effect should be performed.

Bottom Line: Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling.Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells.Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China.

ABSTRACT
DNA methyltransferase inhibitors (MTIs) have recently emerged as promising chemotherapeutic or preventive agents for cancer, despite their poorly characterized mechanisms of action. The present study shows that DNA methylation is integral to the regulation of SH2-containing protein tyrosine phosphatase 1 (SHP1) expression, but not for regulation of suppressors of cytokine signalling (SOCS)1 or SOCS3 in colorectal cancer (CRC) cells. SHP1 expression correlates with down-regulation of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3/STAT5) signalling, which is mediated in part by tyrosine dephosphorylation events and modulation of the proteasome pathway. Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling. We demonstrate that 5-aza-dc suppresses growth of CRC cells, and induces G2 cell cycle arrest and apoptosis through regulation of downstream targets of JAK2/STAT3/STAT5 signalling including Bcl-2, p16(ink4a), p21(waf1/cip1) and p27(kip1). Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells. Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling. This study represents the first evidence towards establishing a mechanistic link between inhibition of JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells that may lead to the use of MTIs as a therapeutic intervention for human colorectal cancer.

Show MeSH
Related in: MedlinePlus