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

ABSTRACT: 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/?-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/?-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/?-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/?-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/?-catenin-MACC1 signaling axis.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC6079074 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Kim Hwa Jin HJ Moon Sue Jin SJ Kim Seok-Hyung SH Heo Kyu K Kim Jeong Hoon JH

Cell death & disease 20180806 8

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 co ...[more]

PMID: 30082743

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Project description:Lysine-specific demethylase 1 (LSD1) is widely involved in the proliferation, invasion, and metastasis of cancers. However, it is uncertain whether LSD1 plays a role in facilitating colon cancer progression. Here, we have clarified the molecular mechanism by which LSD1 interacts with X-ray repair cross complementing protein 5 (Ku80) to promote colon cancer progression by directly targeting forehead protein transcription factor 2 (FOXF2). First, the interacting proteins of LSD1 were identified by immunoprecipitation and mass spectrometry. The expression of Ku80 and FOXF2 in colon cancer was detected using immunohistochemistry, real-time quantitative transcription polymerase chain reaction, and western blot. Next, the proliferation, invasion, and metastasis of colon cancer in vitro and in vivo were detected by methyl thiazolyl tetrazolium, 5-ethynyl-20-deoxyuridine, colony formation, wound healing, and nude mice xenograft model assays, respectively. Chromatin immunoprecipitation (ChIP) and ChIP-PCR were performed to investigate the molecular mechanism of LSD1 and Ku80 in colon cancer. Our results indicated that Ku80 expression was positively correlated with the invasion and migration of colon cancer cells, and negatively correlated with FOXF2 expression. More importantly, the high expression of Ku80 and the low expression of FOXF2 were particularly associated with driving the progression of colon cancer. Ku80 knockdown and LSD1 silencing inhibited the proliferation, migration, and invasion of colon cancer in vitro and in vivo. Mechanically, LSD1 interacts with Ku80 and also binds directly to the 687-887-bp portion of the FOXF2 promoter region. The upregulated methylation level of H3K4me2 in the FOXF2 promoter region facilitated the transcriptional activation of FOXF2, and downregulated protein expression associated with the Wnt/β-catenin signaling pathway. In conclusion, our study suggests that LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80, promoting the malignant biological properties of colon cancer, highlighting the binding of LSD1 and Ku80 as a useful anti-cancer target for colon cancer.

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Dataset Information

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

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

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