Dataset Information

The long noncoding RNA TUG1 is required for TGF-?/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

ABSTRACT: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-?) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-? is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downstream signaling component of TGF-? that can be targeted to impair CRC metastasis. Here, we show that TGF-? promotes CRC migration and upregulates the expression of long-noncoding RNA Taurine Upregulated Gene 1 (TUG1). TUG1 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, and reduced CRC lung metastasis in vivo. TGF-? induced metastasis, and TUG1 knockdown inhibited these effects. In addition, TGF-? could not reverse the anti-metastasis effects of TUG1 knockdown. These data demonstrate that TUG1 is a downstream molecular of TGF-?. Moreover, TWIST1 expression was increased with TGF-? treatment, and TUG1 knockdown decreased TWIST1 expression in CRC cells. TWIST1 knockdown inhibited invasion and EMT in CRC cells; these effects were not changed by simultaneous TUG1 knockdown, indicating that TWIST1 is a downstream mediator of TUG1. Moreover, TUG1 was significantly overexpressed in CRC patients. In conclusion, TGF-? promotes metastasis of CRC via a TUG1/TWIST1/EMT signaling pathway. TUG1 may be a promising drug target to inhibit TGF-? pathway activation in the treatment of CRC.

SUBMITTER: Shen X

PROVIDER: S-EPMC6985237 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The long noncoding RNA TUG1 is required for TGF-β/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

Shen Xuning X Hu Xiu X Mao Jiayan J Wu Ying Y Liu Hao H Shen Jian J Yu Jiayin J Chen Wei W

Cell death & disease 20200127 1

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-β) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-β is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downst ...[more]

PMID: 31988275

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Project description:Simple Summary The epithelial-mesenchymal transition (EMT) program plays a central role in the metastasis of patients with colorectal carcinoma (CRC). However, few studies have investigated the dominant regulatory factors and underlying mechanisms during the EMT process in CRC metastasis. Here we have characterized a novel transcriptionally repressive complex, ZEB2/TWIST1/PRMT5/NuRD, which epigenetically silences E-cadherin, leading to the invasion and metastasis of CRC cells. Our work provides a comprehensive understanding of the epigenetic mechanisms by which the key EMT metastasis driver, E-cadherin, is regulated in CRC, thereby suggesting PRMT5 and HDAC2 inhibitors as potentially therapeutic agents in CRC therapy. Abstract (1) Background: The EMT plays a crucial role in tumor metastasis, which is the major cause for colorectal carcinoma-related mortality. However, the underlying regulators and mechanisms of EMT in CRC metastasis are still poorly understood; (2) Methods: The transcriptional regulators of EMT in CRC and their functions were examined using RT2212PCR, Western blotting, and luciferase reporter assay. The components of ZEB2/TWIST1 complex and their mutual interactions were identified via affinity purification, mass spectrometry, co-immunoprecipitation, and pull-down experiments. The functional mechanisms of ZEB2/TWIST1/PRMT5/NuRD axis were determined by chromatin immunoprecipitation and luciferase reporter assay. The contribution of ZEB2/TWIST1/PRMT5/NuRD complex in the CRC metastasis was investigated using wound healing, transwell assay, and in vivo xenograft mouse model; (3) Results: We found that ZEB2 and TWIST1 were both significantly upregulated in CRC tissues and EMT of CRC cells. ZEB2 could recruit TWIST1 to the E-cadherin promoter and synergistically repressed its transcription. In addition, ZEB2 physically interacted with TWIST1, PRMT5, and the nucleosome remodeling and deacetylase (NuRD) complex to form a novel repressive multicomplex, leading to epigenetic silencing of E-cadherin in CRC cells. Notably, the combined inhibition of ZEB2 and TWIST1 and epigenetic inhibition markedly reduced CRC metastasis in mice; (4) Conclusions: We revealed for the first time that ZEB2 could recruit TWIST1, PRMT5, and NuRD to form a repressive multicomplex and epigenetically suppresses the transcription of E-cadherin, thereby inducing the EMT process and metastasis in CRC. Our results also confirmed the therapeutic potential of epigenetic inhibitors in CRC.

Dataset Information

The long noncoding RNA TUG1 is required for TGF-?/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

Publications

The long noncoding RNA TUG1 is required for TGF-β/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

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