THE ROLE OF THE LIPID ACYLTRANSFERASE LCLAT1 IN THE PI3K/Akt/PTEN SIGNALING PATHWAY

Candidate: Yuchen Zheng
Supervisor: Dr. Roberto Botelho and Dr. Costin Antonescu

ABSTRACT

Triple-negative breast cancer is driven partly by mutations in the PI3K-PI3,4,5P₃-Akt signaling. Headgroups of phosphoinositides (PIPs) are extensively studied. However, acyl profile adds more complexity. In mammalian cells, the most abundant acyl profile of PIPs is 1-stearoyl-2-arachidonoyl. The lysophospholipid acyltransferase LCLAT1 preferentially incorporates stearate at the sn-1 position of lysoPIs. Previously, our labs showed that silencing LCLAT1 in MDA-MB-231 cells decreased PI3,4,5P₃ and reduced Akt activation. Here, we show that LCLAT1 silencing decreased PTEN protein level, a 3-phosphatase, likely due to changes in the transcriptional, post-transcriptional, translational, and post-translational circuits. We found that PTEN protein stability was unchanged, but its mRNA level was reduced, which was unrelated to alternative polyadenylation. We found that LCLAT1 silencing hindered cell proliferation, decreased mRNA abundance of other genes, and downregulated global translation. Our work may be therapeutically valuable as LCLAT1 could affect important cellular processes via regulating PIPs, serving as a potential drug target.