Cargando…
Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1)
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...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724785/ https://www.ncbi.nlm.nih.gov/pubmed/23922913 http://dx.doi.org/10.1371/journal.pone.0070077 |
_version_ | 1782476723003064320 |
---|---|
author | Huang, Zebin Li, Shangze Song, Wei Li, Xin Li, Qinshan Zhang, Zeyan Han, Yongqing Zhang, Xiaodong Miao, Shiying Du, Runlei Wang, Linfang |
author_facet | Huang, Zebin Li, Shangze Song, Wei Li, Xin Li, Qinshan Zhang, Zeyan Han, Yongqing Zhang, Xiaodong Miao, Shiying Du, Runlei Wang, Linfang |
author_sort | Huang, Zebin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3724785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37247852013-08-06 Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) Huang, Zebin Li, Shangze Song, Wei Li, Xin Li, Qinshan Zhang, Zeyan Han, Yongqing Zhang, Xiaodong Miao, Shiying Du, Runlei Wang, Linfang PLoS One Research Article 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. Public Library of Science 2013-07-26 /pmc/articles/PMC3724785/ /pubmed/23922913 http://dx.doi.org/10.1371/journal.pone.0070077 Text en © 2013 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Huang, Zebin Li, Shangze Song, Wei Li, Xin Li, Qinshan Zhang, Zeyan Han, Yongqing Zhang, Xiaodong Miao, Shiying Du, Runlei Wang, Linfang Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title | Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title_full | Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title_fullStr | Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title_full_unstemmed | Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title_short | Lysine-Specific Demethylase 1 (LSD1/KDM1A) Contributes to Colorectal Tumorigenesis via Activation of the Wnt/Β-Catenin Pathway by Down-Regulating Dickkopf-1 (DKK1) |
title_sort | lysine-specific demethylase 1 (lsd1/kdm1a) contributes to colorectal tumorigenesis via activation of the wnt/β-catenin pathway by down-regulating dickkopf-1 (dkk1) |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724785/ https://www.ncbi.nlm.nih.gov/pubmed/23922913 http://dx.doi.org/10.1371/journal.pone.0070077 |
work_keys_str_mv | AT huangzebin lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT lishangze lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT songwei lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT lixin lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT liqinshan lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT zhangzeyan lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT hanyongqing lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT zhangxiaodong lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT miaoshiying lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT durunlei lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 AT wanglinfang lysinespecificdemethylase1lsd1kdm1acontributestocolorectaltumorigenesisviaactivationofthewntbcateninpathwaybydownregulatingdickkopf1dkk1 |