Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation

Anti-tumor immunity through checkpoint inhibitors, specif-ically anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction, is a promising approach for can-cer therapy. However, as early clinical trials indicate that colorectal cancers (CRCs) do not respond well to immune-checkpoint therapies, new effective immunotherapy ap-proaches to CRC warrant further study. Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) reductase (HMGCR), the rate-limiting enzyme of the mevalo-nate (MVA) pathway for the cholesterol biosynthesis. However, little is known about the functions of simvastatin in the regula-tion of immune checkpoints or long noncoding RNA (lncRNA)-mediated immunoregulation in cancer. Here, we found that simvastatin inhibited PD-L1 expression and pro-moted anti-tumor immunity via suppressing the expression of lncRNA SNHG29. Interestingly, SNHG29 interacted with YAP and inhibited phosphorylation and ubiquitination-medi-ated protein degradation of YAP, thereby facilitating downre-gulation of PD-L1 transcriptionally. Patient-derived tumor xenograft (PDX) models and the clinicopathological analysis in samples from CRC patients further supported the role of the lncRNA SNHG29-mediated PD-L1 signaling axis in tumor microenvironment reprogramming. Collectively, our study un -covers simvastatin as a potential therapeutic drug for immuno-therapy in CRC, which suppresses lncRNA SNHG29-mediated YAP activation and promotes anti-tumor immunity by inhibit-ing PD-L1 expression.

Automated summary

Research has shown that simvastatin inhibits PD-L1 expression and promotes anti-tumor immunity by suppressing the expression of lncRNA SNHG29. SNHG29 interacts with YAP and inhibits its degradation, leading to the downregulation of PD-L1.