Table 2.
Histone modification erasers contribute to both pro-hybrid E/M and pro-epithelial processes.
| Hybrid E/M TF protein interaction |
Hybrid E/M TF gene interaction |
Pro-hybrid E/M state function |
Pro-epithelial state function |
Refs | |
|---|---|---|---|---|---|
| Histone lysine de-methylases (KDMs) | |||||
| LSD1 | Snai1 | -- | Essential for Snai1-mediated transcriptional repression; becomes activated by EGFR signaling and induces migration. | Binds to NuRD complex and silences targets of TGF-β signaling. | 90-93 |
| KDM3A/JMJD1 | -- | SNAI2 | Upregulates SNAI2 in response to hypoxia signaling; de-represses lncRNA MALAT1. | -- | 100, 101 |
| KDM4B/JMJD2B | -- | -- | De-represses mesenchymal genes in response to Wnt/β-catenin signaling. | -- | 102 |
| KDM5A/RBP2 | -- | -- | Responds to TGF-β signaling to silence E-cadherin and upregulate N-cadherin; de-represses TNC. | -- | 103, 104 |
| KDM6B/JMJD3 | Snai1/2, Twist1 | -- | De-represses mesenchymal genes in response to TGF-β signaling. | -- | 105 |
| Histone de-acetylases (HDACs) | |||||
| SIRT1 | Zeb1 | -- | Binds Zeb1 and silences E-cadherin expression; SIRT1 silencing abrogates in vitro migration and in vivo metastasis. | Directly de-acetylates SMAD4 protein to dampen TGF-β-induced hybrid E/M. | 106, 107 |
| HDAC1/2 | Snai1, Zeb1 | SNAI2 | (HDAC1/2) Silence many epithelial genes under hybrid E/M conditions. | (HDAC1) Binds SMAR1 remodeling complex and silences SNAI2 expression. | 95-98 |
| HDAC3 | Twist1, Snai1 | -- | Silences several epithelial genes in response to HIF1α-driven hypoxia signaling; binds to Twist1 and Snai1 | -- | 108 |
| NuRD complex (de-acetylase function) | Twist1 | -- | Promotes Twist1-directed E-cadherin silencing. | Silences targets of TGF-β signaling via LDS1. | 93, 99 |