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PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression.

ABSTRACT: The hexosamine biosynthetic pathway (HBP) is connected to abnormal N- and O-linked protein glycosylation in cancer, which performs critical roles in tumorigenesis. However, the regulation mechanisms of HBP and its role in colorectal cancer (CRC) progression remain unexplained. This study analyzed the expression level of phosphoglucomutase 3 (PGM3), a key enzyme in HBP, and identified its function in CRC cell lines. Analysis of publicly available CRC microarray data determined that PGM3 is upregulated in CRC tumor tissues. Furthermore, functional experiments emphasized the significant roles of PGM3 in facilitating CRC cell proliferation and migration. Mechanistically, we demonstrated that the activity of β-catenin in CRC was maintained by PGM3-mediated O-GlcNAcylation. PGM3 knockdown or inhibition of O-GlcNAc transferase decreased β-catenin activity and the expression levels of its downstream targets. Collectively, our findings indicate that PGM3 exhibits tumor-promoting roles by elevating O-GlcNAcylation level and maintaining β-catenin activity, and might serve as a prognostic biomarker and treatment target in CRC.

SUBMITTER: Zhang N

PROVIDER: S-EPMC9554164 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression.

Zhang Nan N Liu Si S Xu Junxuan J Ning Tingting T Xie Sian S Min Li L Zhu Shengquan S Zhang Shutian S Zhu Shengtao S

Experimental biology and medicine (Maywood, N.J.) 20220620 17

The hexosamine biosynthetic pathway (HBP) is connected to abnormal N- and O-linked protein glycosylation in cancer, which performs critical roles in tumorigenesis. However, the regulation mechanisms of HBP and its role in colorectal cancer (CRC) progression remain unexplained. This study analyzed the expression level of phosphoglucomutase 3 (PGM3), a key enzyme in HBP, and identified its function in CRC cell lines. Analysis of publicly available CRC microarray data determined that PGM3 is upregu ...[more]

PMID: 35723049

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Project description:BackgroundN4-acetylcytidine (ac4C) as a significant RNA modification has been reported to maintain the stability of mRNA and to regulate the translation process. However, the roles of both ac4C and its 'writer' protein N-acetyltransferase 10 (NAT10) played in the disease especially colorectal cancer (CRC) are unclear. At this point, we discover the underlying mechanism of NAT10 modulating the progression of CRC via mRNA ac4C modification.MethodsThe clinical significance of NAT10 was explored based on the TCGA and GEO data sets and the 80 CRC patients cohort of our hospital. qRT-PCR, dot blot, WB, and IHC were performed to detect the level of NAT10 and ac4C modification in CRC tissues and matched adjacent tissues. CCK-8, colony formation, transwell assay, mouse xenograft, and other in vivo and in vitro experiments were conducted to probe the biological functions of NAT10. The potential mechanisms of NAT10 in CRC were clarified by RNA-seq, RIP-seq, acRIP-seq, luciferase reporter assays, etc. RESULTS: The levels of NAT10 and ac4C modification were significantly upregulated. Also, the high expression of NAT10 had important clinical values like poor prognosis, lymph node metastasis, distant metastasis, etc. Furthermore, the in vitro experiments showed that NAT10 could inhibit apoptosis and enhance the proliferation, migration, and invasion of CRC cells and also arrest them in the G2/M phase. The in vivo experiments discovered that NAT10 could promote tumor growth and liver/lung metastasis. In terms of mechanism, NAT10 could mediate the stability of KIF23 mRNA by binding to its mRNA 3'UTR region and up-regulating its mRNA ac4c modification. And then the protein level of KIF23 was elevated to activate the Wnt/β-catenin pathway and more β-catenin was transported into the nucleus which led to the CRC progression. Besides, the inhibitor of NAT10, remodelin, was applied in vitro and vivo which showed an inhibitory effect on the CRC cells.ConclusionsNAT10 promotes the CRC progression through the NAT10/KIF23/GSK-3β/β-catenin axis and its expression is mediated by GSK-3β which forms a feedback loop. Our findings provide a potential prognosis or therapeutic target for CRC and remodelin deserves more attention.

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.

Dataset Information

PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression.

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PGM3 regulates beta-catenin activity to promote colorectal cancer cell progression.

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