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基于全基因组 CRISPR-Cas9 筛选的 Wnt/β-catenin 信号通路研究鉴定出结直肠癌的治疗靶点。

Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signaling identifies therapeutic targets for colorectal cancer.

机构信息

Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.

出版信息

Sci Adv. 2021 May 19;7(21). doi: 10.1126/sciadv.abf2567. Print 2021 May.

DOI:10.1126/sciadv.abf2567
PMID:34138730
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8133758/
Abstract

Aberrant activation of Wnt/β-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin-mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of β-catenin to consensus DNA motifs and the transcription of β-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for β-catenin-driven malignancies.

摘要

Wnt/β-catenin 通路的异常激活是结直肠癌（CRC）生长的关键驱动因素，具有重要的治疗意义。在这项研究中，我们进行了全面的 CRISPR 筛选，以探究 CRC 细胞中 Wnt/β-catenin 信号的调控网络。我们发现，人工 TOP 报告基因活性与 β-catenin 介导的内源性转录之间存在显著差异，以及 T 细胞因子/淋巴增强因子转录因子在转导β-catenin 信号中的冗余作用。综合功能基因组筛选和网络分析揭示了β-catenin 转录输出的独特表观遗传调控因子，包括组蛋白赖氨酸甲基转移酶 2A 癌蛋白（KMT2A/Mll1）。通过整合表观基因组学和转录谱分析方法，我们表明 KMT2A 的缺失会降低β-catenin 与共识 DNA 基序的结合以及 CRC 中β-catenin 靶基因的转录。这些结果表明，KMT2A 可能是 CRC 的一个有前途的靶点，并强调了利用表观遗传调控作为β-catenin 驱动的恶性肿瘤的治疗策略的更广泛潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/63d3ce2415a8/abf2567-F7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/5be4f45ac0d2/abf2567-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/918056026599/abf2567-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/c3fe562aec63/abf2567-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/6bd89137e247/abf2567-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/1ab3a50bbd85/abf2567-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/89f2c185be08/abf2567-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/63d3ce2415a8/abf2567-F7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/5be4f45ac0d2/abf2567-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/918056026599/abf2567-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/c3fe562aec63/abf2567-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/6bd89137e247/abf2567-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/1ab3a50bbd85/abf2567-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/89f2c185be08/abf2567-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b1d/8133758/63d3ce2415a8/abf2567-F7.jpg

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本文引用的文献

[1]
The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.

Nat Commun. 2020-12-21

[2]
Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/.

Proc Natl Acad Sci U S A. 2020-10-20

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Technol Cancer Res Treat. 2020

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Pharmacol Res. 2020-10

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A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production.

Cell Rep. 2019-12-3

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KMT2A histone methyltransferase contributes to colorectal cancer development by promoting cathepsin Z transcriptional activation.

Cancer Med. 2019-5-15

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Cell Rep. 2019-1-8

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Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.

J Clin Invest. 2018-11-12

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Genes (Basel). 2018-9-1

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Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction.

J Med Chem. 2018-5-23

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