Allosteric Regulation of IGF2BP1 as a Novel Strategy for the Activation of Tumor Immune Microenvironment,ACS Central Science

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Allosteric Regulation of IGF2BP1 as a Novel Strategy for the Activation of Tumor Immune Microenvironment
ACS Central Science ( IF 12.7 ) Pub Date : 2022-05-17 , DOI: 10.1021/acscentsci.2c00107
Yang Liu _{1,

2} , Qiang Guo ₁ , Heng Yang ₁ , Xiao-Wen Zhang ₁ , Na Feng ₁ , Jing-Kang Wang ₁ , Ting-Ting Liu ₁ , Ke-Wu Zeng ₁ , Peng-Fei Tu ₁

Affiliation

Tumor immune microenvironment (TIME) regulators are promising cancer immunotherapeutic targets. IGF2BP1, as a crucial N⁶-methyladenosine (m⁶A) reader protein, recognizes m⁶A 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 m⁶A 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.

中文翻译：

IGF2BP1 的变构调节作为激活肿瘤免疫微环境的新策略

肿瘤免疫微环境 (TIME) 调节剂是有前途的癌症免疫治疗靶点。IGF2BP1 作为一种重要的N ⁶ -甲基腺苷 (m ⁶ A) 读取蛋白，可识别 m ⁶ A 靶转录物，最终导致癌症发展。然而，目前，IGF2BP1在调节TIME中的生物学功能尚不清楚。在这项研究中，我们报道了 IGF2BP1 敲低诱导癌细胞凋亡，从而不仅显着激活免疫细胞浸润，包括 CD4 ⁺、CD8 ⁺ T 细胞、CD56 ⁺ NK 细胞和 F4/80 ⁺巨噬细胞，但也降低了肝细胞癌 (HCC) 中 PD-L1 的表达。然后，化学遗传学鉴定出一种小分子葫芦素 B (CuB)，它直接靶向 KH1-2 结构域中独特位点 (Cys253) 的 IGF2BP1。这导致药理学变构效应阻断 IGF2BP1 对 m ⁶ A mRNA 靶标（如c-MYC ）的识别，这与细胞凋亡和免疫反应高度相关。在体内，CuB通过诱导细胞凋亡表现出明显的抗HCC作用，随后将免疫细胞募集到肿瘤微环境中，并阻断PD-L1的表达。总的来说，IGF2BP1 可以通过介导 TIME 作为抗癌治疗的新药理变构靶点。

更新日期：2022-05-17

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