Lipid metabolism reprogramming roles in mantel cell lymphoma growth and survival

Abstract

Introduction: Metabolic reprogramming is a hallmark of cancer progression. However, there are few studies in mantle cell lymphoma (MCL). Protein arginine methyltransferase 5 (PRMT5), catalyzes monomethylation and symmetric demethylation of arginine residues on histone and nonhistone proteins and participates in tumor progression. This study aimed to investigate the mechanism of PRMT5-induced lipid reprogramming in MCL. Method: Lymph node, bone marrow biopsy, peripheral blood specimens and MCL cell lines were utilized as models. Liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS)-based analysis was performed to measure the steady-state level of metabolites. GSE93291 dataset and immunohistochemistry (IHC) staining were utilized to determine the relationship between expression levels of PRMT5 and patient outcome. CRISPR/Cas9 editing was employed to engineer the loss-of-function models of PRMT5 and other key genes involved in lipid metabolism. Result: Non-targeted LC-MS/MS analysis showed that lipid metabolites were rich in MCL cell lines (Figure 1A and 1B). Through systematic analysis of the relationship between lipid metabolism-related genes and MCL prognosis in GSE93291, PRMT5, SREBP1, SRENP2, FASN and MYC were found to be associated with the overall survival (OS) of MCL patients (Figure 1F–1J), which suggested that lipid metabolism reprogramming may be involved in the development of MCL. IHC staining of PRMT5 in 105 MCL tissues confirmed that elevated PRMT5 expression was significantly associated with poor progression free survival (PFS) (P = 0.039) and OS (P < 0.001) in MCL patients (Figure 1D and 1E). Multivariate Cox regression analysis showed that high PRMT5 expression was an independent prognostic indicator of OS (P = 0.003). Gene transcriptome sequencing showed downregulation of the PRMT5 caused the reduced expression of SREBP1/SREBP2 and FASN and change the expression of lipid metabolite (Figure 1K). PRMT5, SREBP1/SREBP2 and FASN depletion significantly impaired outgrowth and increased apoptosis of MCL cells. In primary tumor samples, MYC protein levels were significantly correlated with PRMT5 protein levels (P < 0.001). PRMT5 knockout blocked MYC mRNA and protein expression, suggesting a requisite role of PRMT5 in MYC transcription regulation. Further molecular biological methods were used to verify that PRMT5 could participate in lipid metabolism reprogramming through MYC by changing the expression levels of SREBP1/SREBP2 and FASN (Figure 1L). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers, Metabolism No conflicts of interests pertinent to the abstract.