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.

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.

• Authors: Hung-Chih Hsu, Yi-Shiuan Liu, Kai-Chi Tseng, Tsai-Sheng Yang, Chien-Yuh Yeh, Jeng-Fu You, Hsin-Yuan Hung, Shu-Jen Chen, Hua-Chien Chen
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 141 Issue 1 Pg. 11-21 (Jan 2015) ISSN: 1432-1335 [Electronic] Germany
• PMID: 25060070 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• CBB1003
• Enzyme Inhibitors
• LGR5 protein, human
• Piperazines
• RNA, Messenger
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Histone Demethylases
• KDM1A protein, human

Topics

• Adenoma (drug therapy, metabolism, pathology)
• Adult
• Aged
• Aged, 80 and over
• Amidines (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Colon (drug effects, metabolism, pathology)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Demethylases (antagonists & inhibitors, genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• Male
• Middle Aged
• Neoplasm Staging
• Piperazines (pharmacology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Rectum (drug effects, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured