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DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer

Metastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function...

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Autores principales: Kim, Hwa Jin, Moon, Sue Jin, Kim, Seok-Hyung, Heo, Kyu, Kim, Jeong Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079074/
https://www.ncbi.nlm.nih.gov/pubmed/30082743
http://dx.doi.org/10.1038/s41419-018-0899-9
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author Kim, Hwa Jin
Moon, Sue Jin
Kim, Seok-Hyung
Heo, Kyu
Kim, Jeong Hoon
author_facet Kim, Hwa Jin
Moon, Sue Jin
Kim, Seok-Hyung
Heo, Kyu
Kim, Jeong Hoon
author_sort Kim, Hwa Jin
collection PubMed
description Metastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function of MACC1 in various types of human malignancies, regulatory mechanisms underlying MACC1 expression remain unclear. Here we report that MACC1 is a direct target of Wnt/β-catenin signaling pathway in colon cancer cells and that DBC1 functions as a coactivator for Wnt-mediated MACC1 expression by promoting the activity of a LEF1/β-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/β-catenin complex formation on the MACC1 enhancer and for long-distance enhancer-promoter interaction of the MACC1 locus. MACC1 expression was increased in colonosphere cells compared to adherent colon cancer cells, and DBC1 overexpression further increased MACC1 expression in colonospheres and promoted sphere-forming abilities of colon cancer cells and drug resistance of colonospheres. Importantly, expressions of MACC1 and DBC1 are positively correlated with each other, upregulated in high-risk groups of colorectal cancer patients, and associated with poor survival. Our results establish MACC1 as a transcriptional target of Wnt/β-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/β-catenin-MACC1 signaling axis.
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spelling pubmed-60790742018-08-07 DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer Kim, Hwa Jin Moon, Sue Jin Kim, Seok-Hyung Heo, Kyu Kim, Jeong Hoon Cell Death Dis Article Metastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function of MACC1 in various types of human malignancies, regulatory mechanisms underlying MACC1 expression remain unclear. Here we report that MACC1 is a direct target of Wnt/β-catenin signaling pathway in colon cancer cells and that DBC1 functions as a coactivator for Wnt-mediated MACC1 expression by promoting the activity of a LEF1/β-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/β-catenin complex formation on the MACC1 enhancer and for long-distance enhancer-promoter interaction of the MACC1 locus. MACC1 expression was increased in colonosphere cells compared to adherent colon cancer cells, and DBC1 overexpression further increased MACC1 expression in colonospheres and promoted sphere-forming abilities of colon cancer cells and drug resistance of colonospheres. Importantly, expressions of MACC1 and DBC1 are positively correlated with each other, upregulated in high-risk groups of colorectal cancer patients, and associated with poor survival. Our results establish MACC1 as a transcriptional target of Wnt/β-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/β-catenin-MACC1 signaling axis. Nature Publishing Group UK 2018-08-06 /pmc/articles/PMC6079074/ /pubmed/30082743 http://dx.doi.org/10.1038/s41419-018-0899-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Kim, Hwa Jin
Moon, Sue Jin
Kim, Seok-Hyung
Heo, Kyu
Kim, Jeong Hoon
DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title_full DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title_fullStr DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title_full_unstemmed DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title_short DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
title_sort dbc1 regulates wnt/β-catenin-mediated expression of macc1, a key regulator of cancer progression, in colon cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079074/
https://www.ncbi.nlm.nih.gov/pubmed/30082743
http://dx.doi.org/10.1038/s41419-018-0899-9
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