Allosteric Regulation of IGF2BP1 as a Novel Strategy for the Activation of Tumor Immune Microenvironment

被引：102

作者：

Liu, Yang ^{[1
,2
]}

Guo, Qiang ^{[1
]}

Yang, Heng ^{[1
]}

Zhang, Xiao-Wen ^{[1
]}

Feng, Na ^{[1
]}

Wang, Jing-Kang ^{[1
]}

Liu, Ting-Ting ^{[1
]}

Zeng, Ke-Wu ^{[1
]}

Tu, Peng-Fei ^{[1
]}

机构：

[1] Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

[2] Peking Univ Third Hosp, Ctr Basic Med Res, Inst Med Innovat & Res, Beijing 100191, Peoples R China

来源：

ACS CENTRAL SCIENCE | 2022年 / 8卷 / 08期

基金：

国家重点研发计划;

关键词：

RNA-BINDING-PROTEINS; COVALENT INHIBITORS; MYC; TARGETS; FAMILY;

D O I：

10.1021/acscentsci.2c00107

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial N-6-methyladenosine (m(6)A) reader protein, recognizes m(6)A target transcripts, ultimately leading to cancer development. However, currently, the biological function of IGF2BP1 in regulating the TIME is not well-understood. In this study, we report that IGF2BP1 knockdown induces cancer cell apoptosis, thereby significantly not only activating immune cell infiltration including CD4(+), CD8(+) T cells, CD56(+) NK cells, and F4/80(+) macrophage but also decreasing PD-L1 expression in hepatocellular carcinoma (HCC). Then, chemical genetics identifies a small-molecule cucurbitacin B (CuB), which directly targets IGF2BP1 at a unique site (Cys253) in the KH1-2 domains. This leads to a pharmacological allosteric effect to block IGF2BP1 recognition of m(6)A mRNA targets such as c-MYC, which is highly associated with cell apoptosis and immune response. In vivo, CuB exhibits an obvious anti-HCC effect through inducing apoptosis and subsequently recruits immune cells to tumor microenvironment as well as blocking PD-L1 expression. Collectively, IGF2BP1 may serve as a novel pharmacological allosteric target for anticancer therapeutics via mediating TIME.

引用

页码：1102 / 1115

页数：14

共 39 条

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