Quantitative Proteomics of Mouse Liver (FTO-KO,WT) in response to DEN injection

ABSTRACT: Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Hendrik Nolte  

LAB HEAD: Thomas Langer

PROVIDER: PXD018223 | Pride | 2020-11-03

REPOSITORIES: Pride