Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1)

Abstract

We collected paired samples of tumor and adjacent normal colorectal tissues from 22 patients with colorectal carcinoma to compare the differences in the expression of lysine specific demethylase 1 (LSD1) in these two tissues. The results showed that in 19 paired samples (86.4%), LSD1 is more highly expressed in tumor tissue than in normal tissue. To explore the role of LSD1 in colorectal tumorigenesis, we used somatic cell gene targeting to generate an LSD1 knockout (KO) HCT 116 human colorectal cancer cell line as a research model. The analysis of phenotypic changes showed that LSD1 KO colorectal cancer cells are less tumorigenic, both in vivo and in vitro. The differential expression analysis of the cells by mRNA sequencing (RNA-Seq) yielded 2,663 differentially expressed genes, and 28 of these genes had highly significant differences (Q <0.01). We then selected the 4 colorectal cancer-related genes ADM, DKK1, HAS3 and SMURF2 for quantitative real-time PCR verification. The results showed that the differences in the expression of ADM, DKK1 and HAS3 were consistent with those measured using the RNA-Seq data. As DKK1 was the gene with the most significant differential expression, we analyzed the key proteins of the DKK1-related Wnt/β-catenin signaling pathway and found that, after knocking out LSD1, the amount of free β-catenin translocated to the nucleus was significantly reduced and that the transcription of the signaling pathway target gene c-Myc was down-regulated. Our studies show that LSD1 activates the Wnt/β-catenin signaling pathway by down-regulating the pathway antagonist DKK1, which may be one of the mechanisms leading to colorectal tumorigenesis.

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

“…However, we did not observe any significant change in global methylation levels upon LSD1 inhibitor treatment, suggesting that some unknown mechanism may compensate for the loss of LSD1 demethylase catalytic activity. The result is similar to the study of Huang et al (2013). Although Hunag et al (2013) found that LSD1 contributes to colorectal tumorigenesis via activation of the Wnt/β-catenin pathway by down-regulating Dickkopf-1 (DKK1) and Ding et al (Ding et al 2013) reported that LSD1 promotes metastasis of colon cancer cells by down-regulating the expression of CDH-1, the role of LSD1 in CRC stem cell has not been elucidated.…”

Long non-coding RNA HOTAIR is a powerful predictor of metastasis and poor prognosis and is associated with epithelial-mesenchymal transition in colon cancer

“…On the other hand, the 3' domain of HOTAIR maintains LSD1-binding activity (15). LSD1, the first identified demethylase that specifically catalyzes the demethylation of histone H3 lysine 4, is believed to be linked to the transcriptional silencing of tumor-suppressor genes (19)(20)(21)(22). Tsai et al (15) suggested that HOTAIR, as a modular scaffold, is required to target both PRC2 and LSD1 to many promoter elements of genes in order to coordinate chromatin modification for gene repression.…”

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

“…Recent studies reported that the expression of Dickkopf-1 (DKK1) was significantly higher in HCT116 cells compared with that in LoVo cells (Yu et al, 2013). DKK1 is one of the key regulators of the Wingless-int (Wnt)/b-catenin signaling pathway, which plays an important role in development and in regulating adult stem cell systems (Huang et al, 2013). Moreover, aberrant regulation of this pathway promotes tumorigenesis of human colorectal cancer (Klaus & Birchmeier, 2008).…”