• Open Access

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

Authors

  • Hua Xiong,

    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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  • Zhao-Fei Chen,

    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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  • Qin-Chuan Liang,

    1. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
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  • Wan Du,

    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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  • Hui-Min Chen,

    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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  • Wen-Yu Su,

    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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  • Guo-Qiang Chen,

    1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao-Tong University School of Medicine, Luwan, Shanghai, China
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  • Ze-Guang Han,

    1. Shanghai-Ministry Key Laboratory of Disease and Health Genomics, Chinese National Human Genome Center, Shanghai, China
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  • Jing-Yuan Fang

    Corresponding author
    1. Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
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Correspondence to: Jing-Yuan FANG, M.D., Ph.D., Shanghai Institute of Digestive Disease, Ren-Ji Hospital, 145 Middle Shandong Road, Shanghai, 200001, China.
Tel.: 0086-21-63200874
Fax: 0086-21-63266027
E-mail: jingyuanfang@yahoo.com

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, p16ink4a, p21waf1/cip1 and p27kip1. 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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