Abstract
Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.
Highlights
Protein arginine methylation is a common posttranslational modification that affects the function of many histones and non-histone proteins and regulates important cellular processes [1]
The results indicated that the short hairpin RNA (shRNA) sequence targeting the third site of PRMT5 was most effect to knock down PRMT5 expression (Figure 1A)
We knocked down PRMT5 expression in another human lung cancer line, HCC827, and the Lewis lung carcinoma (LLC) mouse lung cancer cell line to further verify the function of PRMT5
Summary
Protein arginine methylation is a common posttranslational modification that affects the function of many histones and non-histone proteins and regulates important cellular processes [1]. PRMT5 Inhibition Promotes PD-L1 Expression histones, such as H3, H4, and H2A, and non-histone proteins, such as p53, p65, and HOXA9, to regulate various cellular processes including mRNA splicing, DNA repair, signal transduction, cell cycle, apoptosis, and oncogenesis [3, 4]. Histone posttranslational methylation leads to changes in chromatin composition and configuration, is a principal component of epigenetic-mediated gene expression, and induces transcriptional activation or repression [5]. PRMT5 drives or represses gene expression by modifying histone residues. It dimethylates histone H3R2me2s, drives H3K4me, and promotes gene expression, whereas it dimethylates H3R8 and H4R3 to repress gene activation [4, 6]
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