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Title:
m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling | Molecular Cancer
Description:
Background Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. Methods qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. Results Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. Conclusions Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.
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Keywords {š}
alkbh, cells, cancer, wif, expression, pdac, fig, article, wnt, cell, pancreatic, google, scholar, signaling, additional, file, gemcitabine, figure, overexpression, aspc, tumor, modification, rna, bxpc, mrna, levels, mmp, mia, mice, control, cas, proliferation, protein, xenograft, paca, formation, data, qrtpcr, human, colony, wang, migration, treatment, methylation, genes, cancers, panc, quantification, analysis, invasion,
Topics {āļø}
augmented wnt/pi3k-akt signaling gemcitabine-treated patient-derived xenograft poly-a-purified rna heat-induced antigen recovery treated-patient-derived xenograft article download pdf twisted developmental biology article google scholar wnt/beta-catenin pathway wnt/beta-catenin signaling wnt/β-catenin pathway avidin-biotin peroxidase complex wnt/β-catenin signaling [27 wnt/β-catenin signaling considered statistically significant β-catenin protein levels kaplan-meier analysis indicating network-based methods alkbh5-mediated m6a modification m6a-seq m6a-ip gemcitabine-treated pdx model biological processes including β-catenin mrna transcripts anti-α-catenin antibody pancreatic cancer stem paraffin-embedded tissues cut genes differentially expressed mia paca-2-alkbh5 cells mediating wnt signaling pancreatic ductal adenocarcinoma pancreatic cancer cells targeting beta-catenin including cell proliferation cancer cell proliferation m6a demethylase alkbh5 human colorectal carcinoma human neuroendocrine tumors pancreatic cancer tissues increased cell proliferation cancer stem cell cancer stem cell diminished promoter activations related subjects mediating methylation reversal privacy choices/manage cookies β-catenin promoter activity n6-methyladenosine mettl3 cell proliferation program tumor growth rate nat rev cancer
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headline:m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling
description:Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.
datePublished:2020-01-06T00:00:00Z
dateModified:2020-01-06T00:00:00Z
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keywords:
Pancreatic cancer
m6A methylation
Chemo-resistance
ALKBH5
WIF-1
Wnt
Cancer Research
Oncology
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headline:m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling
description:Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.
datePublished:2020-01-06T00:00:00Z
dateModified:2020-01-06T00:00:00Z
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Pancreatic cancer
m6A methylation
Chemo-resistance
ALKBH5
WIF-1
Wnt
Cancer Research
Oncology
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