Molecular Mechanisms of TWIST1-Regulated Transcription in EMT and Cancer Metastasis

Authors

Xiaobin Yu
Tao He
Zhangwei Tong
Lan Liao
Shixia Huang
Walid D Fakhouri
Dean P Edwards
Jianming Xu

Language

English

Publication Date

11-6-2023

Journal

EMBO Reports

DOI

10.15252/embr.202356902

PMID

37680145

PMCID

PMC10626429

PubMedCentral® Posted Date

9-8-2023

PubMedCentral® Full Text Version

Post-print

Abstract

TWIST1 induces epithelial-to-mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N-terminus antagonizes TWIST1-regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60-Com) via its N-terminus. Non-acetylated TWIST1-K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1-acK73/76 binds BRD8, a component of TIP60-Com that also binds histone H4-acK5/8, to recruit TIP60-Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60-Com interaction and TIP60-Com recruitment to TWIST1-activated genes, resulting in decreasing TWIST1-activated target gene expression and cancer metastasis. Both TWIST1/NuRD and TWIST1/TIP60-Com complexes are required for TWIST1 to promote EMT, proliferation, and metastasis at full capacity. Therefore, the diacetylation status of TWIST1-K73/76 dictates whether TWIST1 interacts either with NuRD to repress epithelial genes, or with TIP60-Com to activate mesenchymal genes and MYC. Since BRD8 is essential for TWIST1-acK73/76 and TIP60-Com interaction, targeting BRD8 could be a means to inhibit TWIST1-activated gene expression.

Keywords

Humans, Neoplasms, Epithelial-Mesenchymal Transition, Nuclear Proteins, Twist-Related Protein 1, acetylation, BRD8, epithelial‐to‐mesenchymal transition, NuRD, TIP60, TWIST1, Cancer; Chromatin, Transcription & Genomics; Signal Transduction

Published Open-Access

yes

Recommended Citation

Yu, Xiaobin; He, Tao; Tong, Zhangwei; et al., "Molecular Mechanisms of TWIST1-Regulated Transcription in EMT and Cancer Metastasis" (2023). Faculty and Staff Publications. 1957.
https://digitalcommons.library.tmc.edu/baylor_docs/1957