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组蛋白 H3k27 乙酰化激活时钟基因 TIMELESS 通过与肌球蛋白-9 结合促进结直肠癌肿瘤发生。

Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9.

机构信息

Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.

Department of Anatomy, Histology and Embryology, Nanjing Medical University, Xuehai Building, Rm D509, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.

出版信息

J Exp Clin Cancer Res. 2021 May 10;40(1):162. doi: 10.1186/s13046-021-01936-4.

DOI:10.1186/s13046-021-01936-4
PMID:33971927
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8108341/
Abstract

BACKGROUND

Colorectal cancer (CRC) is a common tumor characterized by its high mortality. However, the underlying molecular mechanisms that drive CRC tumorigenesis are unclear. Clock genes have important roles in tumor development. In the present study, the expression and functions of clock gene TIMELESS (encoding the Timeless protein) in CRC were investigated.

METHODS

Immunohistochemistry, cell proliferation, migration, invasion, EMT and xenograft tumor experiments were used to prove the function of Timeless in the tumorigenesis of CRC. Immunoprecipitation, mass spectrometry, Immunofluorescence and Chromatin immunoprecipitation (ChIP) were utilized to clarify the mechanism of Timeless in regulating CRC tumorigenesis.

RESULTS

We found that Timeless was upregulated in CRC tissues compared with corresponding normal tissues and its expression was closely associated with the TNM stages and overall survival of CRC patients. Functional studies demonstrated that Timeless promoted the proliferation, invasion, and EMT of CRC cells in vitro and in vivo. Mechanistic investigations showed that Timeless activated the β-catenin signal pathway by binding to Myosin-9, which binds to β-catenin to induce its nuclear translocation. The upregulation of Timeless was attributed to CREB-binding protein (CBP)/p300-mediated H3K27 acetylation of the promoter region of Timeless.

CONCLUSION

Timeless regulates the tumorigenesis of CRC by binding to and regulating myosin-9, suggesting Timeless might be a potential prognostic biomarker and therapeutic target for CRC.

摘要

背景

结直肠癌（CRC）是一种常见的肿瘤，其死亡率较高。然而，导致 CRC 肿瘤发生的潜在分子机制尚不清楚。时钟基因在肿瘤发生发展中具有重要作用。本研究旨在探讨时钟基因 TIMELESS（编码 Timeless 蛋白）在 CRC 中的表达及功能。

方法

采用免疫组化、细胞增殖、迁移、侵袭、上皮间质转化（EMT）和异种移植瘤实验，证明 Timeless 在 CRC 肿瘤发生中的作用。通过免疫沉淀、质谱分析、免疫荧光和染色质免疫沉淀（ChIP）实验，阐明 Timeless 调节 CRC 肿瘤发生的机制。

结果

与相应的正常组织相比，我们发现 Timeless 在 CRC 组织中上调，其表达与 CRC 患者的 TNM 分期和总生存期密切相关。功能研究表明，Timeless 促进了 CRC 细胞的体外和体内增殖、侵袭和 EMT。机制研究表明，Timeless 通过与肌球蛋白-9（Myosin-9）结合来激活 β-catenin 信号通路，Myosin-9 与 β-catenin 结合诱导其核转位。Timeless 的上调归因于 CREB 结合蛋白（CBP）/p300 介导的 Timeless 启动子区域的 H3K27 乙酰化。

结论

Timeless 通过与肌球蛋白-9 结合并调节其活性来调节 CRC 的肿瘤发生，提示 Timeless 可能是 CRC 的一个潜在预后标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/430c948a6ec4/13046_2021_1936_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/d37da5a73e77/13046_2021_1936_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/f7f500f39d4d/13046_2021_1936_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/1fbc68efbb95/13046_2021_1936_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/05c52743c4bc/13046_2021_1936_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/61b8bd57008e/13046_2021_1936_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/c9676a65f4a4/13046_2021_1936_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/8d26459e8fa2/13046_2021_1936_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/60321417b3c6/13046_2021_1936_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/430c948a6ec4/13046_2021_1936_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/d37da5a73e77/13046_2021_1936_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/f7f500f39d4d/13046_2021_1936_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/1fbc68efbb95/13046_2021_1936_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/05c52743c4bc/13046_2021_1936_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/61b8bd57008e/13046_2021_1936_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/c9676a65f4a4/13046_2021_1936_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/8d26459e8fa2/13046_2021_1936_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/60321417b3c6/13046_2021_1936_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/19d8/8108341/430c948a6ec4/13046_2021_1936_Fig9_HTML.jpg

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