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Park, M.K.; Lee, H.; Lee, C.H. ZEB Family Members in Cancer Progression. Encyclopedia. Available online: https://encyclopedia.pub/entry/43184 (accessed on 05 May 2024).
Park MK, Lee H, Lee CH. ZEB Family Members in Cancer Progression. Encyclopedia. Available at: https://encyclopedia.pub/entry/43184. Accessed May 05, 2024.
Park, Mi Kyung, Ho Lee, Chang Hoon Lee. "ZEB Family Members in Cancer Progression" Encyclopedia, https://encyclopedia.pub/entry/43184 (accessed May 05, 2024).
Park, M.K., Lee, H., & Lee, C.H. (2023, April 18). ZEB Family Members in Cancer Progression. In Encyclopedia. https://encyclopedia.pub/entry/43184
Park, Mi Kyung, et al. "ZEB Family Members in Cancer Progression." Encyclopedia. Web. 18 April, 2023.
ZEB Family Members in Cancer Progression
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This entry is adapted from the peer-reviewed paper 10.3390/ijms232315127

Post-translational modification (PTM), the essential regulatory mechanisms of proteins, play essential roles in physiological and pathological processes. In addition, PTM functions in tumour development and progression. Zinc finger E-box binding homeobox (ZEB) family homeodomain transcription factors, such as ZEB1 and ZEB2, play a pivotal role in tumour progression and metastasis by induction epithelial-mesenchymal transition (EMT), with activation of stem cell traits, immune evasion and epigenetic reprogramming.

zinc finger E-box binding homeobox (ZEB) post-translational modifications (PTM) cancer progression

1. Introduction

Cancer-associated mortality represents the second leading cause of death worldwide after cardiovascular disease [1]. Cancer metastasis is the primary cause of cancer mortality, accounting for approximately 90% of tumour-related deaths. The epithelial-mesenchymal transition (EMT) is the tissue repair and developmental process, along with neural crest formation, heart morphogenesis, and mesoderm formation, facilitating gastrulation and secondary palate formation [2][3][4][5]. Moreover, EMT is a vital clue to tumour invasion and metastasis. Zinc finger E-box binding homeobox transcription factors (ZEBs) play a crucial role in the progression and metastasis of various cancers, as EMT-related transcription factors [6][7][8][9][10][11][12][13], in the regulation of DNA damage repair [14] and neuronal differentiation [15].
Furthermore, ZEBs are associated with the degree of malignancy in various types of cancer and the activation of EMT signalling, which are widely believed to contribute to invasion, metastasis, recurrence and therapeutic resistance. ZEBs are also associated with cancer transformation and EMT. Post-translational modification (PTM) is the enzymatic modification of proteins after synthesis [16] and induces proliferation in cancer progression by regulating the cell cycle, cell survival and cellular signalling [17].

2. ZEB1 and ZEB2 Proteins and Their Physiological Functions

The zinc finger E-box-binding homeobox 1 (ZEB1) is also known as δEF1, ZFHX1A, MEB1, Nil-2-a, TCF8, AREB6, ZFHEP1 or BZP [18]. The human ZEB1 gene is located on chromosome 10p11.22 and encodes the 1117 amino acid ZEB1 protein [19]. Zinc finger E-box-binding homeobox 2 (ZEB2) is identified as KIAA0569, SIP1, ZFHX1B and ZFX1B; the human ZEB2 gene is located on chromosome 2q22.3 and encodes a 1214 amino acid protein [20]. The ZEB proteins consist of a homeodomain (HD) in the middle of the structure and other protein binding domains, including the SMAD interaction domain (SID), which regulates the transforming growth factor beta (TGFβ)-mediated transcription with bone morphogenetic proteins (BMP) signalling, zinc finger domain (ZFD), coactivator binding domain (CBD), CtBP interaction domain (CID) and the p300-CBP-associated factor (P/CAF) binding domain, which control EMT as a trigger of for tumour progression and metastasis (Figure 1) [21][22][23][24][25].
Figure 1. Overviews of ZEB1 and ZEB2 PTMs. It is characterized by the presence of two zinc finger clusters, one at each end (NZF and CZF) and located homeodomain (HD). Other domains are P300-P/CAF interaction domain (CBD), the Smad binding domain (SBD) and the CtBP interaction domain (CID). ZF, zinc finger; NLS, nuclear localization signal. PTM site. Black, Phosphorylation (ZEB1, ZEB2); Sky blue, Ubiquitination (ZEB1, ZEB2); Red, SUMOylation (ZEB1, ZEB2); Green, Di-methylation (ZEB1, ZEB2); Orange, Acetylation (ZEB2).
ZEB1 can recruit cosuppressors or coactivators by high-affinity binding of the ZFD to specific DNA binding sites (CACCTG), upregulating or downregulating its target genes [26]. ZEB proteins bind to SMADs. However, while ZEB-1/dEF1 synergises with SMAD proteins to activate transcription, promote osteoblastic differentiation and induce cell growth arrest, ZEB1 is expressed during development in the central nervous system, heart, skeletal muscle and haematopoietic cells; this plays pivotal roles in regulating development, differentiation and maintenance [23][27].
Additionally, ZEB1 is a transcriptional activator, or, has repressor functions in normal regulatory processes and dysregulated progress, such as cancer progression and metastasis. ZEB2 is expressed during the development in the neural tube and crest cells and all parts of the developing forebrain. In addition, it plays a role as a regulator of the TGFβ/BMP signal pathway. When the TGFβ/BMP factor binds to the receptor, the SMAD proteins are translocated to the nucleus, activating the target genes’ transcription. ZEB2 interacts with R-SMADs to induce embryo neutralisation and disrupts the expression of the activin-dependent Brachyury gene in Xenopus [28][29]. ZEB2 also endures post-transcriptional regulation by several micro-RNAs (miRNAs), such as postnatal brain miRNA (miR9) [30].

3. ZEB1 and ZEB2 in Cancer Progression

ZEB protein is involved in tumour invasion and metastasis in the invasive front of carcinomas by EMT induction. ZEB1 is highly expressed in several tumours, including breast [6][7], pancreatic [9][24][31], colorectal [32], gastric [33][34], lung [35][36][37], uterine [38], hepatocellular carcinoma [39], prostate [40][41] and lymphoma [42] cancers. In these tumours, ZEB1 expression correlates with the loss of E-cadherin and is associated with advanced disease or metastasis, indicating the relevance of ZEB1 induction of EMT and tumour progression [13]. Mechanistically, TGF-β enhances pSMAD2/3 and ZEB1 [43] and ZEB2 [44] expression to increase tumour invasion. The β-catenin translocates into the nucleus to activate ZEB1 [45] transcription. WNT signaling induces ZEB2 expression in tumour metastasis [46]. Activation of MEK1/2 and ERK1/2 promotes tumour progression by ZEB1 [47] and ZEB2 [48]. TNF-α induces the mesenchymal phenotype via NF-κB, ZEB1 and ZEB2 signaling [49]. Fos-related antigen 1 (Fra-1) is a member of the Fos family that dimerizes with Jun proteins to form AP-1. Fra-1 induces EMT by modulating ZEB1, ZEB2 and TGFβ expression [50]. E2F1, a transcription factor, regulates EMT and metastasis by increasing ZEB2 expression in small-cell lung cancer [51]. ZEB2 is coexpressed with the POU family and upregulates EMT induction [52]. PRC2-mediated ZEB2 expression represses PTM by SUMOlation [53]. FOXO1, a member of the FOXO family of transcription factors (FoxOs), binds the ZEB2 promoter and destabilizes the ZEB2 mRNA. As a result, it inhibits ZEB2-induced EMT [54] (Figure 2). Loss of E-cadherin is a casual prerequisite for progressing from adenocarcinoma to invasive carcinomas by genetic and epigenetic mechanisms during malignant transformation [8]. In analogy with their function, ZEB1 lose the epithelial phenotype and gain the mesenchymal phenotype with motile and migratory abilities in cancer [5]. Moreover, ZEB1/miR-200 plays an essential role in embryonic development and malignant tumour progression [55]. ZEB1 is an essential factor in the regulation of the initiation and development of tumours through EMT (Figure 3).
Figure 2. Mechanisms of ZEB family in cancer progression and metastasis. EGFR, WNT, tumor necrosis factor-a (TNFa), transforming growth factor beta (TGF-b), Fos-related antigen 1 (Fra-1), miR-200 family, POU family, PRC2 and FOXO-1 trigger expression of ZEB1 proteins. As a result, the ZEB family controls cancer progression and metastasis.
Figure 3. Regulation of ZEB family in cancer progression. PTMs, EMT, miRNA and immune checkpoints of ZEBs functionally are linked to cancer progression.
In the genetically engineered mouse model (GEMM), ZEB1 knockout mice die perinatally, exhibiting respiratory failure; severe T cell deficiency of the thymus; and various skeletal defects, including craniofacial abnormalities, limb and sternum defects, and malformed ribs [56]. These developmental defects are associated with mesenchymal-epithelial transition, as evidenced by the re-expression of E-cadherin and loss of vimentin in several tissues and embryonic fibroblasts [57]. In addition, ZEB1 is a crucial factor for local invasion, colonisation capacities and distant metastasis in the Pdx1-Cre-mediated mutant KRAS and the p53 pancreatic cancer mouse (KPC) model [9]. ZEB1 was also shown to affect p53 and RB-dependent oncosuppressive pathways and to prevent senescence and apoptosis, two critical barriers against tumour development. In line with this notion, mouse embryonic fibroblasts (MEF) from ZEB1 knockout mice undergo early replicative senescence.

4. Post-Translational Modifications of ZEBs in Cancer Progression

PTMs are covalent modifications that occur after the transcript has been translated into proteins, such as the ZEB1, ZEB2, SNAIL (SNAI1), SLUG (SNAI2) and twist-related (Twist 1) proteins. The human SNAI1 is located on chromosome 20q13.13 and encodes the 264-amino acid Snail protein. It is a member of the Snail superfamily, and acts as a transcriptional regulator of EMT [58]. The human SNAI2 is located on chromosome 8q11.21 and encodes the 268-amino acid Slug protein. Slug binds the nuclear receptor corepressor (NCoR) and C-terminal binding protein 1 (CtBP1) to stabilize Slug and inhibit the expression of E-cadherin [59]. The human Twist1 genes are located on chromosome 7p21.2 and encodes the 202-amino acid Twist1 protein. The Twist1 plays a critical role in the progression of cancer by modulating EMT [60][61]. These covalent modifications include adding a modifying chemical group or another small protein to one or more residues of the target protein [62]. PTM can occur within the protein on single or multiple residues, undergoing the same or different modifications [63]. Table 1 provides an overview of the molecular mechanisms and biological functions of PTMs of ZEBs in cancer progression.
Table 1. Functions of ZEBs-PTMs.

PTMs Type

PTM Sites

Kinase/Enzyme

Biological Function

Cancer Type

Ref.

ZEB1

Phosphorylation

Thr867

ERK

Inhibition of the nuclear localisation of ZEB1

-

[64]

Thr851, Ser852, Ser853

PKC

Inhibition of the nuclear localisation of ZEB1

-

[64]

Ser585

ATM

Promotes DDR and tumour radioresistance

BC

[14]

SUMOylation

-

Senp1

Promotes migration and EMT.

HCC

[65]

Ubiquitination

-

Siah

Promotes cell proliferation and invasion

BC

[66]

Deubiquitination

N-terminal

USP51

Promotes cell proliferation and invasion

BC

[67]
 

CSN5

Promotes metastasis and EMT

RCC

[68]
 

USP18

Promotes EMT

ESCC

[69]

Acetylation

Lys741, Lys774, Lys775

P/CAF

Promotes the formation of a p300-SMAD transcriptional complex

  

[22]

N-terminal

TIP60

Corepressor of the ZEB

T lymphoma

[70]

Deacetylation

  

HDAC1/2

Promotes EMT

PAAD

[71][72]

ZEB2

Phosphorylation

Ser705, Tyr802

GSK-3β

Promotes metastasis and chemoresistance

CRC

[73]

SUMOylation

Lys391, Lys866

Pc2

Promotes EMT

  

[53]

Ubiquitination

Lys48

FBXO45

Promotes EMT initiation and cancer progression

  

[74]
 

FBXL14

Promotes EMT

COAD

[75]
 

FBXW7

Promotes metastasis and chemoresistance

CRC

[73]

BC, breast cancer; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; ESCC, oesophageal squamous cell carcinomas; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; PAAD, pancreatic adenocarcinoma; CRC, colorectal cancer; COAD, colon adenocarcinoma; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; ATM, ataxia–telangiectasia mutated kinase; USP51, ubiquitin-specific peptidase 51; CSN5, COP9 signalosome subunit 5; USP18, ubiquitin-specific peptidase 18; PCAF, p300/CBP-associated factor; TIP60, tat-interacting protein of 60 kDa; HDAC1/2, histone deacetylase 1/2; GSK3β, glycogen synthase kinase 3 beta; FBXO45, F-box only protein 45; FBXL14, F-Box and leucine-rich repeat protein 14; FBXW7, F-box/WD repeat-containing protein 7.

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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Mi Kyung Park
,
Ho Lee
,
Chang Hoon Lee
View Times: 246
Revisions: 2 times (View History)
Update Date: 19 Apr 2023
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