Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma
文献类型：期刊论文
| 作者 | Luo, Yuhong1; Gao, Yuqing2,3; Liu, Weiwei4; Yang, Yuan5; Jiang, Jie6; Wang, Ying2; Tang, Wei7; Yang, Shoumei1; Sun, Lulu1; Cai, Jie1 |
| 刊名 | HEPATOLOGY
 |
| 出版日期 | 2021-10 |
| 卷号 | 74期号:4页码:1932-1951 |
| ISSN号 | 0270-9139 |
| DOI | 10.1002/hep.31864 |
| 文献子类 | Article |
| 英文摘要 | Background and Aims HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC. Approach and Results Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti-programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. Conclusions This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of immune-cold tumor to ICT. |
| WOS关键词 | C-MYC ; CANCER |
| WOS研究方向 | Gastroenterology & Hepatology |
| 语种 | 英语 |
| 出版者 | LIPPINCOTT WILLIAMS & WILKINS |
| WOS记录号 | WOS:000672905500001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309376]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Chen, Lei; Xie, Cen; Gonzalez, Frank J. |
| 作者单位 | 1.NCI, NIH, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Mod, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing, Peoples R China; 4.Tongji Univ, Shanghai Tenth Peoples Hosp, Dept Lab Med & Cent Lab, Shanghai, Peoples R China; 5.Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Shanghai, Peoples R China; 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China; 7.NCI, NIH, Ctr Canc Res, Lab Human Carcinogenesis,Mol Epidemiol Sect, Bethesda, MD 20892 USA; 8.Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC USA; 9.Capital Med Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China; 10.Minist Educ, Key Lab Remodeling Related Cardiovasc Dis, Beijing, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Luo, Yuhong,Gao, Yuqing,Liu, Weiwei,et al. Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma[J]. HEPATOLOGY,2021,74(4):1932-1951. |
| APA | Luo, Yuhong.,Gao, Yuqing.,Liu, Weiwei.,Yang, Yuan.,Jiang, Jie.,...&Gonzalez, Frank J..(2021).Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma.HEPATOLOGY,74(4),1932-1951. |
| MLA | Luo, Yuhong,et al."Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma".HEPATOLOGY 74.4(2021):1932-1951. |
入库方式： OAI收割
来源：上海药物研究所
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