m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling

Molecular Cancer

Yin Bi¹  Yihua Yang¹  Yunshan Wang²  Fumio Shimamoto³  Bo Tang⁴  Yan Wang⁴  Songqing He⁴  Min Kang⁵ 

[1] Center of Reproductive Medicine, The First Affiliated Hospital of Guangxi Medical University;Department of Clinical Laboratory, The Second Hospital of Shandong University;Department of Health Sciences, Hiroshima Shudo University;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University;Department of Radiation Oncology, the First Affiliated Hospital of Guangxi Medical University;

关键词: Pancreatic cancer;    m6A methylation;    Chemo-resistance;    ALKBH5;    WIF-1;    Wnt;   

DOI  :  10.1186/s12943-019-1128-6

来源: DOAJ

【 摘 要 】

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 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.

【 授权许可】

Unknown