ZEB2/TWIST1/PRMT5/NuRD Multicomplex Contributes to the Epigenetic Regulation of EMT and Metastasis in Colorectal Carcinoma

• Published in: Cancers Vol. 14; no. 14; p. 3426
• Main Authors: Zheng, Yayuan, Dai, Mingrui, Dong, Yue, Yu, Hanqiao, Liu, Tianfu, Feng, Xuejian, Yu, Bin, Zhang, Haihong, Wu, Jiaxin, Kong, Wei, Yu, Xianghui, Wu, Hui
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 14.07.2022; MDPI
• Subjects: Antibodies; Cancer; Cell differentiation; Cervical cancer; Chemotherapy; Chromatin; Colorectal cancer; Colorectal carcinoma; Development and progression; E-cadherin; Epigenetic inheritance; Epigenetics; Epithelial cells; Genetic aspects; Glycerol; HDAC2 protein; Histone deacetylase; Immunoprecipitation; Lymphatic system; Mass spectrometry; Mass spectroscopy; Medical prognosis; Mesenchyme; Metastases; Metastasis; NuRD protein; Oncology, Experimental; Radiation therapy; Scientific imaging; Stem cells; Transcription; Tumors; Western blotting; Wound healing; Xenografts; China; St Louis Missouri; United States > US
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14143426

(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.