N6-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability

Gene. 2020 Mar 20;731:144348. doi: 10.1016/j.gene.2020.144348. Epub 2020 Jan 9.

Abstract

Mounting evidence demonstrates that N6-methyladenosine (m6A) play critical roles of m6A in the epigenetic regulation, especially for human cancer. The m6A modification is installed by methyltransferase and erased demethylases, leading to the significant modification for gene expression and cell fate. Here, we investigated the biological roles and mechanism of demethylase alkylation repair homolog protein 5 (ALKBH5) in the non-small cell lung cancer (NSCLC). Results revealed that ALKBH5 was ectopically up-regulated in the NSCLC tissue and cells, and closely correlated with the poor prognosis. Functionally, ALKBH5 promoted the proliferation and reduced apoptosis of NSCLC cells in vitro, and knockdown of ALKBH5 repressed the tumor growth in vivo. Mechanistically, RNA immunoprecipitation sequencing (RIP-Seq) revealed that ALKBH5 targeted the TIMP3. Moreover, ALKBH5 repressed TIMP3 mRNA stability and protein production. In conclusion, the present research confirmed the ALKBH5/TIMP3 pathway in the NSCLC oncogenesis progress, providing a novel insight for the epitranscriptome and potential therapeutic target for NSCLC.

Keywords: ALKBH5; M(6)A; Non-small cell lung cancer; TIMP3.

MeSH terms

  • A549 Cells
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • AlkB Homolog 5, RNA Demethylase / genetics
  • AlkB Homolog 5, RNA Demethylase / metabolism*
  • AlkB Homolog 5, RNA Demethylase / physiology*
  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Epigenesis, Genetic / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA Stability / genetics*
  • RNA, Messenger / metabolism
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*

Substances

  • RNA, Messenger
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • N-methyladenosine
  • ALKBH5 protein, human
  • AlkB Homolog 5, RNA Demethylase
  • Adenosine