Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation
Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation
复制标题
靶向胆固醇生物合成通过抑制长非编码 RNA SNHG29 介导的 YAP 激活来促进抗肿瘤免疫
DOI：
10.1016/j.ymthe.2021.05.012
复制
发表时间：
2021-10-06
影响因子：
12.4
通讯作者：
Li, Jianming
中科院分区：
文献类型：
--
作者：
Ni, Wen;Mo, Hui;Li, Jianming
通过检查点抑制剂，特别是抗程序性死亡1 (PD-1)/程序性死亡配体1 （PD-L1）的相互作用，抗肿瘤免疫是一种很有前途的癌症治疗方法。然而，由于早期临床试验表明结直肠癌（CRC）对免疫检查点疗法的反应不佳，新的有效的CRC免疫治疗方法值得进一步研究。辛伐他汀是一种3-羟基-3-甲基戊二酰辅酶A （CoA）还原酶（HMGCR）抑制剂，是胆固醇生物合成mevalo- ate （MVA）途径的限速酶。然而，辛伐他汀在癌症中调节免疫检查点或长链非编码RNA （lncRNA）介导的免疫调节中的功能知之甚少。本研究发现辛伐他汀通过抑制lncRNA SNHG29的表达抑制PD-L1表达，促进抗肿瘤免疫。有趣的是，SNHG29与YAP相互作用，抑制YAP磷酸化和泛素化介导的蛋白降解，从而促进PD-L1转录下调。患者源性肿瘤异种移植（PDX）模型和CRC患者样本的临床病理分析进一步支持了lncRNA snhg29介导的PD-L1信号轴在肿瘤微环境重编程中的作用。综上所述，我们的研究揭示了辛伐他汀作为一种潜在的CRC免疫治疗药物，可以抑制lncRNA snhg29介导的YAP激活，并通过抑制PD-L1表达来促进抗肿瘤免疫。
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.