An AKT/PRMT5/SREBP1 axis in lung adenocarcinoma regulates de novo lipogenesis and tumor growth

Abstract

Protein kinase B (AKT) hyperactivation and de novo lipogenesis are both common in tumor progression. Sterol regulatory element‐binding protein 1 (SREBP1) is the master regulator for tumor lipid metabolism, and protein arginine methyltransferase 5 (PRMT5) is an enzyme that can catalyze symmetric dimethyl arginine (SDMA) modification of the mature form of SREBP1 (mSREBP1) to induce its hyperactivation. Here, we report that SDMA‐modified mSREBP1 (mSREBP1‐SDMA) was overexpressed and correlated with Ser473‐phosphorylated AKT (AKT‐473P) expression and poor patient outcomes in human lung adenocarcinomas. Furthermore, patients with AKT‐473P and mSREBP1‐SDMA coexpression showed the worst prognosis. Mechanistic investigation revealed that AKT activation upregulated SREBP1 at both the transcriptional and post‐translational levels, whereas PRMT5 knockdown reversed AKT signaling‐mediated mSREBP1 ubiquitin‐proteasome pathway stabilization at the post‐translational level. Meanwhile, AKT activation promoted nuclear PRMT5 to the cytoplasm without changing total PRMT5 expression, and the transported cytoplasmic PRMT5 (cPRMT5) induced by AKT activation showed a strong mSREBP1‐binding ability. Immunohistochemical assay indicated that AKT‐473P and mSREBP1‐SDMA were positively correlated with cPRMT5 in lung adenocarcinomas, and high cPRMT5 levels in tumors were associated with poor patient outcomes. Additionally, PRMT5 knockdown reversed AKT activation‐induced lipid synthesis and growth advantage of lung adenocarcinoma cells both in vitro and in vivo. Finally, we defined an AKT/PRMT5/SREBP1 axis involved in de novo lipogenesis and the growth of lung cancer. Our data also support that cPRMT5 is a potential therapeutic target for hyperactive AKT‐driven lung adenocarcinoma.

Abstract

In this research, we defined an AKT/PRMT5/SREBP1 axis involved in de novo lipogenesis and growth of lung cancer. Our data also support that PRMT5 in the cytoplasm is a potential therapeutic target for hyperactive AKT‐driven lung adenocarcinoma.