m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling
Abstract 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 N 6 -methyladenosine (m 6 A) RNA modification has emerged as a new layer of epigenetic gene regulati...
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Published in | Molecular cancer Vol. 19; no. 1; pp. 1 - 15 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
BioMed Central Ltd
06.01.2020
BioMed Central BMC |
Subjects | |
Online Access | Get full text |
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Summary: | Abstract
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 N
6
-methyladenosine (m
6
A) 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. m
6
A-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 m
6
A 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 m
6
A 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 m
6
A methylation in PDAC. |
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ISSN: | 1476-4598 1476-4598 |
DOI: | 10.1186/s12943-019-1128-6 |