Alternative polyadenylation of glutaminase (GLS) in cancer
Cancer cells reprogram their metabolism towards aerobic glycolysis and elevated glutaminolysis, which contributes to the aggressive phenotype. Glutaminase (GLS1) is a key enzyme that regulates both glutaminolysis and glycolysis. There are two isoforms of GLS1 with alternative polyadenylation sites: GAC and KGA. GAC is the better adapted isoform to supply for the increased tumor metabolic needs and positive associated with cell proliferation and tumor progression. We have observed that CFIm25 is a key splicing and 3’ UTR APA regulator for GAC and KGA isoform selection. We are focused on the mechanism of this selection of GAC and KGA and their critical role in tumorigenesis. We use a CRISPR/Cas9 knock in strategy to generate a mCherry/GLS1 reporter system to investigate metabolic reprogram in a wide type of cancer.
3’ UTR APA regulator CFIm25 in neural plasticity and gliomagenisis
More than 70% genes contain proximal and distal polyadenylation sites in mammalian cells. In normal brain, the transcripts prefer to use distal poly(A) site, but in cancers including glioblastoma, a more proximal poly(A) site (pPAS) is chosen and results in shorter mRNA. CFIm25 is a key regulator in the process of 3’ UTR alternative polyadenylation. The reduced 3’UTR length removes negative regulatory elements, therefore increasing protein expression and promoting cell proliferation, differentiation, transformation and tumor progression. We are focused on the biological function of CFIm25 in neuron development and glioma formation. We use a conditional knockout CFIm25 mouse combines with GFAP-Cre/ Syn-Cre mouse to address these two key issues.