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CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Lysine-specific demethylase 1 (LSD1) was highly expressed in several malignancies and had been implicated in pathological processes of cancer cells. However, the role of LSD1 in colorectal cancer (CRC) carcinogenesis, prognosis and treatment remains uncharacterized.

Methods

In this study, we examined LSD1 expression in paraffin-embedded CRC specimens from 295 patients, including 65 patients with paired samples of colorectal carcinoma, adjacent adenoma and normal colorectal tissues. Using an LSD1 inhibitor, CBB1003, as a probe, we studied the association between LSD1 and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a CRC stem cell marker involved in carcinogenesis. The anti-tumor effects of CBB1003 on CRC cells were also examined.

Results

LSD1 expression was significantly elevated in colorectal tumor tissues compared with adjacent adenoma and normal colorectal tissues (P < 0.001), and LSD1 levels were significantly correlated with an advanced AJCC T stage (P = 0.012) and distant metastasis (P = 0.004). CBB1003 inhibited CRC cell proliferation and colony formation. In cultured CRC cells, inhibiting LSD1 activity by CBB1003 caused a decrease in LGR5 levels while overexpression of LGR5 reduced CBB1003-induced cell death. We also observed the inactivation of β-catenin/TCF signaling after CBB1003 treatment, consistent with the positive correlations among LSD1, LGR5, β-catenin and c-Myc expression in human colon tumor and adenoma tissues.

Conclusion

Our result suggested that LSD1 overexpression promotes CRC development and that the LSD1 inhibitor inhibits CRC cell growth by down-regulating LGR5 levels and inactivates the Wnt/β-catenin pathway. Thus, LSD1 and its inhibitor might provide a new target or a useful strategy for therapy of CRC.

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Acknowledgments

This work was supported by grants from Chang Gung Memorial Hospital, Taiwan (CMRPG3B1361) to H.C. Hsu. We thank the Pathology Core of the MMRC at CGU for assistance with immunohistochemical staining and quantification.

Conflict of interest

No potential conflicts of interest are disclosed.

Author information

Authors and Affiliations

  1. Division of Hematology-Oncology, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Hung-Chih Hsu & Tsai-Sheng Yang

  2. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Hung-Chih Hsu

  3. College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Tsai-Sheng Yang, Chien-Yuh Yeh, Jeng-Fu You & Hsin-Yuan Hung

  4. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Yi-Shiuan Liu, Kai-Chi Tseng, Shu-Jen Chen & Hua-Chien Chen

  5. Molecular Medicine Research Center, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Shu-Jen Chen & Hua-Chien Chen

  6. Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Chien-Yuh Yeh, Jeng-Fu You & Hsin-Yuan Hung

  7. Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 333, Taiwan, R.O.C

    Hua-Chien Chen

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  1. Hung-Chih Hsu
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  2. Yi-Shiuan Liu
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Correspondence to Hua-Chien Chen.

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Hsu, HC., Liu, YS., Tseng, KC. et al. CBB1003, a lysine-specific demethylase 1 inhibitor, suppresses colorectal cancer cells growth through down-regulation of leucine-rich repeat-containing G-protein-coupled receptor 5 expression. J Cancer Res Clin Oncol 141, 11–21 (2015). https://doi.org/10.1007/s00432-014-1782-4

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  • DOI: https://doi.org/10.1007/s00432-014-1782-4

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